Pharmaceutically active uridine esters

ABSTRACT

The present invention relates to novel uridine esters of the general formula 
                         
wherein
     R represents a carboxylic acid residue, preferably a fatty acid residue and R′ represents hydrogen or a hydroxy group, their use as pharmaceutically active agents against a variety of diseases, methods for the preparation of said uridine esters and pharmaceutical compositions containing at least one uridine ester as active ingredient. The present invention relates also to a drug combination comprising free fatty acids and/or fatty acid esters and uridine, deoxyuridine, uridine monophosphate and/or deoxyuridine monophosphate, and to the use of such a drug combination.

This application is a Divisional of application Ser. No. 10/476,287filed on Oct. 29, 2003 and for which priority is claimed under 35 U.S.C.§ 120. Application Ser. No. 10/476,287 is the national phase of PCTInternational Application No. PCT/EP02/04725 filed on Apr. 29, 2002under 35 U.S.C. § 371. The entire contents of each of theabove-identified applications are hereby incorporated by reference. Thisapplication also claims priority of Application No. 011 10 608.5 filedin Europe on Apr. 30, 2001, Provisional Application No. 60/288,090 filedin the United States on May 3, 2001, Application No. 011 24 879.6 filedin Europe on Oct. 18, 2001, and Provisional Application No. 60/330,429filed in the United States on Oct. 22, 2001 under 35 U.S.C. § 119.

The present invention relates to novel uridine esters, their use aspharmaceutically active agents against a variety of diseases, methodsfor the preparation of said uridine esters and pharmaceuticalcompositions containing at least one uridine ester as active ingredient.The present invention relates also to a drug combination comprising freefatty acids and/or fatty acid esters and uridine, deoxyuridine, uridinemonophosphate and/or deoxyuridine monophosphate, and to the use of sucha drug combination.

BACKGROUND OF THE INVENTION

Fatty Acids:

Carboxylic acids occur in many molecular forms. At first it must berecalled that if the majority of the fatty acids found in lipids aremonocarboxylic acids, some of the fatty acids are dicarboxylic andconstitute important metabolic products of the previous ones.

To describe precisely the structure of a fatty acid molecule, one mustgive the length of the carbon chain (number of carbon atoms), the numberof double bonds and also the exact position of these double bonds. Thiswill define the biological reactivity of the fatty acid molecule.

Most fatty acids are straight-chain compounds with in most cases an evennumber of carbon atoms. Chain-lengths range from 2 to 80 carbon atoms,but commonly from 12 up to 24. With a chain length from 2 to 4 carbonatoms they are called short-chain, from 6 to 10 they are calledmedium-chain and 12 up to 24 they are called long-chain fatty acids.Their physical and biological properties are related to this partitionin 3 classes.

Fatty acids can be further subdivided into well-defined familiesaccording to their structure:

-   -   a) Saturated fatty acids    -   b) Monoenoic fatty acids    -   c) Polyenoic fatty acids        -   methylene interrupted        -   polymethylene interrupted            -   conjugated            -   isolated    -   d) Mono- and multibranched fatty acids    -   e) Ring containing fatty acids        -   cyclopropane acids        -   furanoid acids        -   epoxy acids        -   lipoic acid    -   f) Acetylenic fatty acids    -   g) Hydroxy fatty acids    -   h) Sulfur containing fatty acids    -   i) Dicarboxylic acids    -   j) Fatty acid amides    -   k) Keto fatty acids.

The simplest fatty acids are referred to as saturated fatty acids. Theyhave no unsaturated linkages and cannot be altered by hydrogenation orhalogenation. When double bonds are present, fatty acids are saidunsaturated, monounsaturated (MUFA) if only one double bond is presentand polyunsaturated (PUFA) if they have two or more double bondsgenerally separated by a single methylene group (methylene-interruptedunsaturation).

To describe these unsaturated fatty acids, two ways are offered:

The chemist's terminology:

The carbon atoms are counted from the carboxyl group which put theemphasis on the double bond closest to this group. As an example: 18:2Δ9,12-octadecadienoic acid or cis-9, cis-12-octadecadienoic acid, thetrivial name: linoleic acid. The double bonds have usually a Z (cis)configuration but can have also a E (trans) configuration.

The biochemist's and physiologist's terminology:

The double bonds are counted from the methyl group determining themetabolic family, noted by n-x (n being the total number of carbonatoms, x the position of the last double bond). The other double bondsare deduced from the first one by adding 3 (this is the most frequentstructure, non-conjugated fatty acids, but sometimes by adding 2, thesedouble bonds are said conjugated).

Thus linoleic acid (cf. FIG. 1 a) or cis-9, cis-12-octadecadienoic acidis also named in the shorthand nomenclature 18:2 (n-6). This compoundhas 18 carbon atoms, 2 double bonds and 6 carbon atoms from the lastdouble bond to the terminal methyl group. In the old literature it wasdesignated 18:2ω6. 18−6=12, 12−3=9 hence D9,12.

Saturated fatty acids have commonly straight chains and even carbonnumber (n=4−30). They have the general formula: CH₃(CH₂)_(n)COOH. Table1 summarizes some saturated acids and their corresponding trivial names.

TABLE 1 Most common saturated fatty acids Shorthand Systematic nameTrivial name designation Butanoic acid Butyric acid  4:0 Hexanoic acidCaproic acid  6:0 Octanoic acid Caprylic acid  8:0 Decanoic acid Capricacid 10:0 Dodecanoic acid Lauric acid 12:0 Tetradecanoic acid Myristicacid 14:0 Hexadecanoic acid Palmitic acid 16:0 Heptadecanoic acidMargaric acid 17:0 Octadecanoic acid Stearic acid 18:0 Eicosanoic acidArachidic acid 20:0 Docosanoic acid Behenic acid 22:0 Tetracosanoic acidLignoceric acid 24:0

Monoenoic fatty acids are monounsaturated normal fatty acids which arewidespread in the living world where they occur mostly as theircis-isomers. They have the general structureCH₃(CH₂)_(x)CH═CH(CH₂)_(y)COOH. They can have the unique double bond ina number of different positions, but the most common are of the n-9series, as oleic acid from olive oil (cis-9-octadecenoic acid) and fromquite all seed oils. Some important monoenoic acids are listed below:

TABLE 2 Monoenoic fatty acids Systematic name Trivial name Shorthanddesignation cis-9-tetradecenoic acid Myristoleic acid 14:1(n-5)cis-9-hexadecenoic acid Palmitoleic acid 16:1(n-7) cis-6-octadecenoicacid Petroselinic acid 18:1(n-12) cis-9-octadecenoic acid Oleic acid18:1(n-9) cis-11-octadecenoic acid Vaccenic acid 18:1(n-7)cis-9-eicosenoic acid Gadoleic acid 20:1(n-11) cis-11-eicosenoic acidGondoic acid 20:1(n-9) cis-13-docosenoic acid Erucic acid 22:1(n-9)cis-15-tetracosenoic acid Nervonic acid 24:1(n-9)

Oleic acid is probably the most common fatty acid (60-70% in olive oil).Several positional isomers of oleic acid exist with the cis double bondin the (n-12) or (n-7) position but trans-isomers are known: Elaidicacid (t9-octadecenoic acid) and t-vaccenic acid (t11-octadecenoic acid)are found in the rumen and in lipids of ruminant animals.

An unusual trans fatty acid, t3-hexadecenoic acid (trans-16:1 n-13),occurs in eukaryotic photosynthetic membranes from higher plants andgreen algae.

Polyenoic fatty acids are also called polyunsaturated fatty acids(PUFA). These fatty acids have 2 or more cis double bonds which are mostfrequently separated from each other by a single methylene group(methylene-interrupted polyenes). Linoleic acid is a typical member ofthis group. Some other polyunsaturated fatty acids undergo a migrationof one of their double bonds which are not again methylene-interruptedand are known as conjugated fatty acids. Some unusual fatty acids dohave not the regular structure with a methylene group between two doublebonds, but are polymethylene-interrupted polyenes. They are found incertain classes of plants, marine invertebrates and insects. Brominatedlong-chain fatty acids have been isolated from phospholipids ofprimitive marine animals such as sponges.

The most important polyenoic fatty acids can be grouped into 2 serieswith a common structural feature: CH₃(CH₂)_(x)CH═CH— with x=4 for the(n-6) series and with x=1 for the (n-3) series. Eicosapentaenoic acid isa common polyene of the (n-3) series having the double bonds in the 5,8, 11, 14, and 17 positions. Table 3 summarizes the most commonpolyenoic fatty acids.

TABLE 3 The most common polyenoic fatty acids are listed below:Shorthand Systematic name Trivial name designation 9,12-octadecadienoicacid Linoleic acid 18:2(n-6) 6,9,12-octadecatrienoic acid γ-Linolenicacid 18:3(n-6) 8,11,14-eicosatrienoic acid Dihomo-γ-linolenic 20:3(n-6)acid 5,8,11,14-eicosatetraenoic acid Arachidonic acid 20:4(n-6)7,10,13,16-docosatetraenoic acid — 22:4(n-6)4,7,10,13,16-docosapentaenoic acid — 22:5(n-6) 9,12,15-octadecatrienoicacid α-Linolenic acid 18:3(n-3) 6,9,12,15-octadecatetraenoic acidStearidonic acid 18:4(n-3) 8,11,14,17-eicosatetraenoic acid — 20:4(n-3)5,8,11,14,17-eicosapentaenoic acid EPA 20:5(n-3)7,10,13,16,19-docosapentaenoic acid DPA 22:5(n-3)4,7,10,13,16,19-docosahexaenoic DHA 22:6(n-3) acid 5,8,11-eicosatrienoicacid Mead acid 20:3(n-9)

The most common polyene acids are octadecatrienoic acids (7 species areknown). Eleostearic acid (9c11t13t) is found in tong oil and had anindustrial importance, calendic acid (8t10t12c) is found in Calendulaofficinalis and catalpic acid (9c11t13c) is found in Catalpa ovata.

Recently, novel polyene fatty acids with different chain lengths andvarying unsaturation were described: 16:5, 18:4, 20:5, 20:6, andunexpectedly 22:7. All these species have in common 4 conjugated all-cisdouble bonds as in 18:4 with their position in 6, 8, 10, and 12, thenovel conjugated docosaheptadecanoic acid having its double bonds in 4,7, 9, 11, 13, 16, and 19, it was named stellaheptaenoic acid.

Among the unsaturated polymethylene-interrupted fatty acids found in theplant kingdom those with a cis-5 ethylenic bond are present in varioussources. The three most frequent fatty acids with that structure aretaxoleic acid (all-cis-5,9-18:2), pinolenic acid (all-cis-5,9,12-18:3)which is found in seeds of conifers, Teucrium and also in tall oil, andsciadonic acid (all-cis-5,11,14-20:3). These fatty acids are present inseed oil at levels from about 1% up to 25%. Similar species with 4double bonds are also described.

Some isoprenoid fat acids are known. In this group, the most interestingis retinoic acid (cf. FIG. 1 a) which derives from retinol and hasimportant functions in cell regulation.

Mono- and multibranched fatty acids, preferably monomethyl branchedfatty acids are found in animal and microbial lipids, e.g. mycobacteria.As for hydrocarbons, they have generally either an iso- or ananteiso-structure. For instance, 14-methyl pentadecanoic acid(isopalmitic acid) is of the iso-series and 13-methyl pentadecanoic acidis of the corresponding anteiso-series. Further examples for branchedfatty acids are pristanic acid and phytanic acid as shown in FIG. 1 a.

Some fatty acids contain either in the chain a cyclopropane ring(present in bacterial lipids) or a cyclopropene ring (present in someseed oils), or at the end of the chain a cyclopentene ring (seed oils).Among cyclopropane acids, lactobacillic acid(11,12-methyleneoctadecanoic acid) is found mainly in gram-negativebacteriae. Another cyclopropane fatty acid (9,10-methylenehexadecanoicacid) was recently shown to be present in phospholipids of heart andliver mitochondria.

Cyclopropene acids are found in Malvales seed oils, and Baobab, Kapokand Mowrah seed oils. Among cyclopentenyl acids, Chaulmoogric acid isfound in chaulmoogra oil from seeds of Flacourtiaceae (Hydnocarpus),which was used in folk medicine for treatment of leprosy.

Epoxy acids are present in a number of seed oils. The natural speciesare all C18 compounds, saturated on unsaturated. For example,9,10-epoxystearic and 9,10-epoxyoctadec-12-enoic (coronaric acid) acidsare found in sunflower seeds (Chrysanthemum).

Lipoic acid (cf. FIG. 1 b) was first considered as a microbial growthfactor but it was found not only in yeast but also in beef liver fromwhich it was first isolated in pure form. Lipoic acid was named alsothioctic acid or 1,2-dithiolane-3-pentanoic acid. After its absorption,this acid is reduced enzymatically by NADH or NADPH to dihydrolipoicacid (or 6,8-dithiane octanoic acid) in various tissues.

First shown necessary for bacteria, lipoic acid was demonstrated to be acoenzyme in the glycine cleavage system and in the dehydrogenasecomplex. Now, lipoic acid is considered as an efficient antioxidantsince with its reduced form it constitutes a redox couple via modulationof NADH/NAD ratio. Consequently, lipoic acid has gained a specialinterest as a therapeutic agent. It can scavenge hydroxyl and peroxylradicals but also chelates transition metals. It is also considered thatlipoic acid is perhaps the most powerful of all the antioxidants, it mayoffer an efficient protection against many heart diseases, it iscurrently used to relieve the complications of diabetes.

Acetylenic fatty acids, also known as ethynoic acids, include fattyacids which contain a triple bond and eventually one or two doublebonds. For instance, tariric acid (6-octadecynoic acid) was found intariri seeds from Picramnia sow, a plant indigenous to Guatemala. Table4 shows further examples of acetylenic fatty acids.

TABLE 4 Acetylenic fatty acids Systematic name Trivial name6-octadecynoic acid Tariric acid t11-octadecen-9-ynoic acid Santalbic orXimenynic acid 9-octadecynoic acid Stearolic acid 6-octadecen-9-ynoicacid 6,9-octadecenynoic acid t10-heptadecen-8-ynoic acid Pyrulic acid9-octadecen-12-ynoic acid Crepenynic acid t7,t11-octadecadiene-9-ynoicacid Heisteric acid t8,t10-octadecadiene-12-ynoic acid —5,8,11,14-eicosatetraynoic acid ETYA

In hydroxy fatty acids the hydroxyl group may occur at various positionsin the carbon chain which can be saturated or monoenoic. Somepolyhydroxy fatty acids are known, which are most frequently produced bylipoxygenase activities. 2-Hydroxy acids (or α-hydroxy acids) are foundin plants (chain from 12 up to 24 carbon atoms) and in animal woolwaxes, skin lipids and specialized tissues, mainly in brain.2-Hydroxytetracosanoic acid (cerebronic acid) and2-hydroxy-15-tetracosenoic acid (hydroxynervonic acid) are constituentsof the ceramide part of cerebrosides and 3-hydroxy acids (or β-hydroxyacids) occur in some bacterial lipids. Further examples are ricinoleicacid (12-hydroxy-9-octadecenoic acid) which characterizes castor beanoil and lesquerolic acid, the C20 homologue of ricinoleic acid(14-hydroxy-11-eicosenoic acid).

Although the dicarboxylic acids do not occur in appreciable amounts ascomponents of animal or vegetal lipids, they are in general importantmetabolic products of fatty acids since they originate from them byoxidation. They have the general type formula: HOOC—(CH₂)_(n)—COOH.Short-chain dicarboxylic acids are of great importance in the generalmetabolism and up to n=3 they cannot be considered as lipids since theirwater solubility is important. The simplest of these intermediates isoxalic acid (n=0), the others are malonic (n=1), succinic (n=2) andglutaric (n=3) acids. The other lipid members of the group found innatural products or from synthesis have a “n” value from 4 up to 21.Examples thereof are: adipic acid (n=4), pimelic acid (n=5), subericacid (n=6), azelaic acid (n=7), sebacic acid (n=8), brassylic acid(n=11), and thapsic acid (n=14).

Ribose and Deoxyribose:

Ribose and deoxyribose are pentoses. Ribose is also called ribofuranosebecause of the structural relationship to furane. The only structuraldifference between ribose and deoxyribose is the loss of an hydroxygroup in position 2′C of the heterocyclic ring. FIG. 2 shows thestructures of ribose and deoxyribose.

Nucleosides and Nucleotides:

These are compounds in which a purine or pyrimidine base is covalentlybound to a sugar. If the base is bound to ribose the result is aribonucleoside (base+sugar=nucleoside), and if bound to deoxyribose thenthe nucleoside is deoxyribonucleoside. In deoxyribose the OH-group on2′C is replaced with hydrogen so becomes deoxy.

The bonding between the base and the sugar involves 1′C OH-group of thesugar, and the N9 nitrogen of a purine or N1 of a pyrimidine in anN-beta-glycosidic linkage. The nucleosides containing deoxyribosepossess the same type of glycosidic linkage.

FIG. 2 shows the three purine bases uracil, cytosine, and thymine.

TABLE 5 Nomenclature Ribonucleotide-5- Base Ribonucleoside monophosphateAdenine Adenosine (A) AMP Guanine Guanosine (G) GMP Uracil Uridine (U)UMP Cytosine Cytidine (C) CMP Thymine Thymidine (T) TMPDeoxyRibonucleotide-5- Base DeoxyRibonucleoside monophosphate AdenineDeoxyadenosine (dA) dAMP Guanine Deoxyguanosine (dG) dGMP UracilDeoxyuridine (dU) dUMP Cytosine Deoxycytidine (dC) dCMP ThymineDeoxythymidine (dT) dTMP

In order to distinguish the numbering of the sugar ring and numbering ofthe bases the sugar numbers are primed, e.g. 3′ 5′. Thus, 5′ refers to5′C of the sugar ring.

These are phosphate esters of the nucleosides and they are fairly strongacids. The phosphoric acid is always esterified to the sugar group(base+sugar+phosphate=nucleotide). The phosphoric acid could be locatedon the 2′, 3′ or 5′C of the sugar residue. However naturalribonucleotides and deoxyribonucleotides have the phosphoric acid on the5′C position.

The phosphoric acid can undergo further phosphorylation to producediphosphates and triphosphates, e.g. ADP and ATP. So for each nucleotidemonophosphate there is also a nucleotide diphosphate and a nucleotidetriphosphate. The di and tri nucleotides do not occur in DNA or RNA onlythe monophosphate nucleotides. The di and triphosphate nucleotides dooccur naturally, and play very important roles in many aspects ofbiochemical metabolism.

Object of the present invention is to provide novel compounds and noveldrug combinations which can be used for prophylaxis and/or treatment ofa variety of diseases and disorders comprising diabetes mellitus Type Iand Type II, inflammation, cancer, necrosis, gastric ulcers,neurodegenerative diseases (Alzheimer's disease, Parkinson's disease),neuropathic diseases, neuropathic pain and polyneuropathy, peripheraland/or central nerve diseases, degradation of the peripheral and/orcentral nerve system, heavy metal poisoning, ishemic diseases andishemic heart disease, liver diseases and dysfunction of liver,allergies, cardiovascular diseases, Chlamydia pneumoniae, and retroviralinfections (HIV, AIDS), together with methods for said treatment andpharmaceutical compositions used within said methods.

This object is solved by the disclosure of the independent claims.Further advantageous features, aspects and details of the invention areevident from the dependent claims, the description, the examples and thefigures of the present application.

DESCRIPTION OF THE INVENTION

The present invention relates to compounds having the general formula(I):

wherein

-   R represents R″—COO;-   R′ represents hydrogen or a hydroxy group;-   R″ represents a alkyl chain with 8 to 30 carbon atoms, a    monobranched or multibranched alkyl chain with 8 to 30 carbon atoms,    a monoenoic alkyl chain with 8 to 30 carbon atoms, a monoenoic    branched alkyl chain with 8 to 30 carbon atoms, a polyenoic alkyl    chain with 8 to 30 carbon atoms, a polyenoic branched alkyl chain    with 8 to 30 carbon atoms, a branched or unbranched alkyl chain with    8 to 30 carbon atoms containing a carbocyclic or heterocyclic ring,    a monoynoic alkyl chain with 8 to 30 carbon atoms, monoynoic    branched alkyl chain with 8 to 30 carbon atoms, a polyynoic alkyl    chain with 8 to 30 carbon atoms, a polyynoic branched alkyl chain    with 8 to 30 carbon atoms, a alkyl chain with 8 to 30 carbon atoms    containing at least one double and one triple bond, a branched alkyl    chain with 8 to 30 carbon atoms containing at least one double and    one triple bond, a hydroxy group or thiol group containing branched    or unbranched and/or saturated or unsaturated alkyl chain with 8 to    30 carbon atoms, and pharmaceutically acceptable salts thereof.

The compounds of the general formula (I) and/or pharmaceuticallyacceptable salts thereof exhibit excellent activity against a variety ofdiseases and disorders and therefore are useful as pharmaceuticallyactive agents.

The compounds according to formula (I) can be synthesized starting fromhydroxy group protected nucleosides or deoxynucleosides. As protectinggroups for the two nucleoside hydroxy groups in position 3 and 4,normally acetals and preferably ketals are used. As protecting groupsfor the deoxynucleoside hydroxy group in position 3, preferably acidsensitive OH-protecting groups for secondary alcohols are used. TheseOH-protected nucleosides or deoxynucleosides are used as startingmaterial and are reacted with carboxylic acid, carboxylic acidhalogenid, carboxylic acid cyanide, carboxylic acid azide, and/orcarboxylic acid anhydride. In the case of a non-activated carboxylicacid is used, reagents such as dicyclohexylcarbodiimide (DCC) are neededin order to support ester formation.

In the case, a carboxylic acid chloride, bromide, cyanide, or azide isused, a base preferably an organic base such as pyridine, dimethylaminopyridine (DMAP), triethylamine, imidazole ect. may be added to thereaction mixture.

Normally equimolar amounts of (deoxy)nucleoside and carboxylic acid orcarboxylic acid derivatives (carboxylic acid halogenids, -cyanides,-azides, -anhydrides) are used within the process, but also a highexcess of one reactant can be used. Preferred solvents comprise polaraprotic solvents such as dichloromethane, chloroform, DMF, or ethers(THF, dioxane, diethylether, TBDME, etc.).

In the last step of the process the OH-protecting group is removedpreferably under smooth acidic conditions optionally at elevatedtemperatures between 80 and 100° C. Solvents such as acetic acid or amixture of water and acetic acid or alcohols such as methanol or ethanolgave good results. A broad variety of organic acids such as benzenesulfonic acids, citric acid, methane sulfonic acid, oxalic acid, etc.may be used in catalytic amounts for ketal and acetal cleavage.

Furthermore, it has turned out to be advantageous to carry out allreaction steps under exclusion of light. Purification of the productswere performed according to standard procedures well known in the stateof the art.

The compounds of the invention are basic and form pharmaceuticallyacceptable salts with organic and inorganic acids. Examples of suitableacids for such acid addition salt formation are hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citricacid, oxalic acid, malonic acid, salicylic acid, p-aminosalicylic acid,malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid,sulfonic acid, phosphonic acid, perchloric acid, nitric acid, formicacid, propionic acid, gluconic acid, lactic acid, tartaric acid,hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid,p-aminobenzoic acid, p-hydroxybenzoic acid, methanesulfonic acid,ethanesulfonic acid, nitrous acid, hydroxyethanesulfonic acid,ethylenesulfonic acid, p-toluenesulfonic acid, naphthylsulfonic acid,sulfanilic acid, camphersulfonic acid, china acid, mandelic acid,o-methylmandelic acid, hydrogen-benzenesulfonic acid, picric acid,adipic acid, d-o-tolyltartaric acid, tartronic acid, α-toluic acid, (o,m, p)-toluic acid, naphthylamine sulfonic acid, and other mineral orcarboxylic acids well known to those skilled in the art. The salts areprepared by contacting the free base form with a sufficient amount ofthe desired acid to produce a salt in the conventional manner.

The free base forms may be regenerated by treating the salt with asuitable dilute aqueous base solution such as dilute aqueous sodiumhydroxide, potassium carbonate, ammonia and sodium bicarbonate. The freebase forms differ from their corresponding salt forms somewhat incertain physical properties, such as solubility in polar solvents, butthe salts are otherwise equivalent to their corresponding free baseforms for purposes of this invention.

The inventive compounds of the general formula (I) exhibit also acidicproperties, because of the uracil moiety and in addition thereto,depending upon the reagents used for the ester formation, e.g. in theevent a dicarboxylic acid is used for ester formation, further acidicgroups are present and the inventive compounds are able to form saltswith organic or inorganic bases, too. Thus, for example, if there arecarboxylic acid substituents in the molecule, salts may be formed withinorganic as well as organic bases such as, for example, NaOH, KOH,NH₄OH, tetraalkylammonium hydroxide, and the like.

Thus, suitable pharmaceutically acceptable salts of the compounds of thepresent invention include addition salts formed with organic orinorganic bases. The salt forming ion derived from such bases can bemetal ions, e.g., aluminum, alkali metal ions, such as sodium orpotassium, alkaline earth metal ions such as calcium or magnesium, or anamine salt ion, of which a number are known for this purpose. Examplesinclude alkali or alkaline-earth hydroxides, alkali or alkaline-earthalkoxides, alkali or alkaline-earth carbonates or bicarbonates, and/ororganic bases such as, i.a., ammonia, primary, secondary and tertiaryamines, such as, e.g., ethanolamine, glucamine, N-methyl- andN,N-dimethylglucamine, arylalkylamines such as dibenzylamine andN,N-dibenzylethylenediamine, lower alkylamines such as methylamine,t-butylamine, procaine, lower alkylpiperidines such asN-ethylpiperidine, cycloalkylamines such as cyclohexylamine ordicyclohexylamine, morpholine, 1-adamantylamine, benzathine, or saltsderived from amino acids like arginine, lysine, ornithine or amides oforiginally neutral or acidic amino acids. The physiologically acceptablesalts such as the sodium or potassium salts and the amino acid salts canbe used medicinally as described below and are preferred.

The compounds of the present invention and/or their pharmaceuticallyacceptable salts are useful for prophylaxis and/or treatment of diabetesmellitus Type I and Type II, inflammation, cancer, necrosis, gastriculcers, neurodegenerative diseases (Alzheimer's disease, Parkinson'sdisease), neuropathic diseases, neuropathic pain and polyneuropathy,peripheral and/or central nerve diseases, degradation of the peripheraland/or central nerve system, heavy metal poisoning, ishemic diseases andishemic heart disease, liver diseases and dysfunction of liver,allergies, cardiovascular diseases, Chlamydia pneumoniae, depression,obesity, stroke, pain, asthma and retroviral infections (HIV, AIDS),including opportunistic infections.

Furthermore, the compounds of the general formula (I) and/orpharmaceutically acceptable salts thereof can be used for themanufacture of a pharmaceutical formulation useful as stimulant drugand/or for prophylaxis and/or treatment of diabetes mellitus Type I andType II, inflammation, cancer, necrosis, gastric ulcers,neurodegenerative diseases (Alzheimer's disease, Parkinson's disease),neuropathic diseases, neuropathic pain and polyneuropathy, peripheraland/or central nerve diseases, degradation of the peripheral and/orcentral nerve system, heavy metal poisoning, ishemic diseases andishemic heart disease, liver diseases and dysfunction of liver,allergies, cardiovascular diseases, Chlamydia pneumoniae, depression,obesity, stroke, pain, and retroviral infections (HIV, AIDS), includingopportunistic infections.

Furthermore, the inventive compounds are useful as stimulant drugs orstimulants. As used herein, the term “stimulant drug” or “stimulant”refers to pharmaceutically active compounds that temporarily increasesthe rate of body functions. The principle pharmacological effect ofstimulant drugs is to stimulate the central nervous system andperipheral system of the body. Some stimulants affect only a specificorgan such as the heart, lungs, brain, or nervous system. Stimulantscomprise substances such as amineptine, amiphenazole, amphetamines,bromantan, caffeine, carphedon, cocaine, ephedrines, fencamfamine,mesocarb, pentylentetrazol, pipradol, salbutamol, salmeterol,terbutaline, and related substances. Stimulants which effect the centralnervous system comprise methcathione, tenamfetamine, MDMA, amfetamine,metamfetamine, fenetylline, methylphenidate, phenmetrazine, amfepramone,mesocarb, pemoline, phentermine, and the like.

Amphetamine-type stimulants can be used for the treatment ofattention-deficit disorder, narcolepsy, and of obesity. Beside that useof stimulants the main therapeutic applications of these psychoactivestimulant drugs are anxiety, depression, epilepsy, psychosis andsleeping disorders.

As used herein the term “stimulate the organism” refers to the effect ofthe inventive compounds according to formula (I) on specific organs andespecially on the central nervous system resulting in a similartherapeutic effect as obtained by the use of a stimulant of the state ofthe art as mentioned above. Thus, the inventive compounds can be used totreat attention-deficit disorder, narcolepsy, obesity, anxiety,depression, epilepsy, psychosis preventation and reversal of fatigue,asthma and sleeping disorders and can replace a common stimulant.

The inventive uridine and deoxyuridine compounds of the general formula(I) comprise a carboxylic acid esters derived from the correspondingfatty acid on position 5′C of the ribose or deoxyribose moiety. Thealkyl chain of said fatty acid comprises 8 to 30 carbon atoms. Preferredare these alkyl chains with 8 or 10 to 24 carbon atoms, more preferably14 to 22 carbon atoms, even more preferably 18 to 22 carbon atoms, andmost preferably 18, 20, or 22 carbon atoms.

Thus, preferred are these inventive compounds wherein R″ represents analkyl chain with 8 to 24 carbon atoms, a monobranched or multibranchedalkyl chain with 8 to 24 carbon atoms, a monoenoic alkyl chain with 8 to24 carbon atoms, a monoenoic branched alkyl chain with 8 to 24 carbonatoms, a polyenoic alkyl chain with 8 to 24 carbon atoms, a polyenoicbranched alkyl chain with 8 to 24 carbon atoms, a branched or unbranchedalkyl chain with 8 to 24 carbon atoms containing a carbocyclic orheterocyclic ring, a monoynoic alkyl chain with 8 to 24 carbon atoms, amonoynoic branched alkyl chain with 8 to 24 carbon atoms, a polyynoicalkyl chain with 8 to 24 carbon atoms, a polyynoic branched alkyl chainwith 8 to 24 carbon atoms, a hydroxy group or thiol group containingbranched or unbranched and/or saturated or unsaturated alkyl chain with8 to 24 carbon atoms and even more preferred are compounds wherein R″represents a monoenoic alkyl chain with 10 to 24 carbon atoms, amonoenoic branched alkyl chain with 10 to 24 carbon atoms, a polyenoicalkyl chain with 10 to 24 carbon atoms, a polyenoic branched alkyl chainwith 10 to 24 carbon atoms, a branched or unbranched alkyl chain with 8to 20 carbon atoms containing a carbocyclic or heterocyclic ring, amonoynoic alkyl chain with 10 to 24 carbon atoms, a monoynoic branchedalkyl chain with 10 to 24 carbon atoms, a polyynoic alkyl chain with 10to 24 carbon atoms, a polyynoic branched alkyl chain with 10 to 24carbon atoms.

Also preferred are carbon chains with an even number of carbon atoms.

Suitable fatty acids which can be used for the formation of carboxylicesters are disclosed in section Fatty acids of the description,especially in tables 1, 2, 3, and 4 of the present application.

Long chain carboxylic acids as listed in Table 1, branched ormultibranched carboxylic acids like isopalmitic acid, pristanic acid orphytanic acid, and monoenoic acids as summarized in Table 2 may be usedfor the synthesis is the inventive compounds of the general formula (I).Preferred is the use of acetylenic acids as shown in Table 4 and hydroxygroup bearing acids like cerebronic acid, hydroxynervonic acid,ricinoleic acid, and lesquerolic acid. More preferred are unsaturatedcarboxylic acids. Examples for the most common unsaturated carboxylicacids are given in Table 3 of the description. Further examples areeleostearic acid, catalpic acid, calendic acid, docosaheptadecanoicacid, taxoleic acid, pinolenic acid, sciadonic acid, and retinoic acid.

Also preferred are carboxylic acids comprising carbocyclic orheterocyclic ring. Examples for ring containing carboxylic acids are11,12-methyleneoctadecanoic acid, 9,10-methylenehexadecanoic acid,coronaric acid, also known as thioctic acid or its reduced form, thedihydrolipoic acid also known as 6,8-dithiane octanoic acid.

Among the unsaturated and ring containing carboxylic acids morepreferred are linoleic acid, γ-linolenic acid, dihomo-γ-linolenic acid,arachidonic acid, 7,10,13,16-docosatetraenoic acid,4,7,10,13,16-docosapentaenoic acid, α-linolenic acid, stearidonic acid,8,11,14,17-eicosatetraenoic acid, EPA, DPA, DHA, Mead acid, (R,S)-lipoicacid, (S)-lipoic acid, (R)-lipoic acid, eleostearic acid, catalpic acid,calendic acid, docosaheptadecanoic acid, taxoleic acid, pinolenic acid,sciadonic acid, and retinoic acid.

Most preferred are the following carboxylic acids: γ-linolenic,α-linolenic, EPA, DHA, (R,S)-lipoic acid, (S)-lipoic acid, and(R)-lipoic acid.

Thus, compounds of the present invention are preferred wherein R″represents dodecanyl, hexadecanyl, octadecanyl, eicosanyl, docosanyl,tetracosanyl, cis-9-tetradecenyl, cis-9-hexadecenyl, cis-6-octadecenyl,cis-9-octadecenyl, cis-11-octadecenyl, cis-9-eicosenyl,cis-11-eicosenyl, cis-13-docosenyl, cis-15-tetracosenyl,9,12-octadecadienyl, 6,9,12-octadecatrienyl, 8,11,14-eicosatrienyl,5,8,11,14-eicosatetraenyl, 7,10,13,16-docosatetraenyl,4,7,10,13,16-docosapentaenyl, 9,12,15-octadecatrienyl,6,9,12,15-octadecatetraenyl, 8,11,14,17-eicosatetraenyl,5,8,11,14,17-eicosapentaenyl, 7,10,13,16,19-docosapentaenyl,4,7,10,13,16,19-docosahexaenyl, 5,8,11-eicosatrienyl,1,2-dithiolane-3-pentanyl, 6,8-dithiane octanyl, docosaheptadecanyl,eleostearyl, calendyl, catalpyl, taxoleyl, pinolenyl, sciadonyl,retinyl, 14-methyl pentadecanyl, pristanyl, phytanyl,11,12-methyleneoctadecanyl, 9,10-methylenehexadecanyl,9,10-epoxystearyl, 9,10-epoxyoctadec-12-enyl, 6-octadecynyl,t11-octadecen-9-ynyl, 9-octadecynyl, 6-octadecen-9-ynyl,t10-heptadecen-8-ynyl, 9-octadecen-12-ynyl, t7,t11-octadecadiene-9-ynyl,t8,t10-octadecadiene-12-ynyl, 5,8,11,14-eicosatetraynyl,2-hydroxytetracosanyl, 2-hydroxy-15-tetracosenyl,12-hydroxy-9-octadecenyl, and 14-hydroxy-11-eicosenyl.

More preferred are these inventive compounds wherein R″ represents9,12-octadecadienyl, 6,9,12-octadecatrienyl, 8,11,14-eicosatrienyl,5,8,11,14-eicosatetraenyl, 9,12,15-octadecatrienyl,6,9,12,15-octadecatetraenyl, 8,11,14,17-eicosatetraenyl,5,8,11,14,17-eicosapentaenyl, 7,10,13,16,19-docosapentaenyl,4,7,10,13,16,19-docosahexaenyl, 5,8,11-eicosatrienyl,1,2-dithiolane-3-pentanyl, and 6,8-dithiane octanyl.

Most preferred are the following compounds of the general formula (I):

-   Compound 1: (2′R,3′S,4′R,5′R)-Octadeca-6,9,12-trienoic acid    5′-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-3′,4′-dihydroxy-tetrahydrofuran-2′-ylmethyl    ester,-   Compound 2: (2′R,3′S,4′R,5′R)-Octadeca-9,12,15-trienoic acid    5′-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-3′,4′-dihydroxy-tetrahydrofuran-2′-ylmethyl    ester,-   Compound 3: (2′R,3′S,4′R,5′R)-Icosa-5,8,11,14,17-pentaenoic acid    5′-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-3′,4′-dihydroxy-tetrahydrofuran-2′-ylmethyl    ester,-   Compound 4: (2′R,3′S,4′R,5′R)-Docosa-4,7,10,13,16,19-hexaenoic acid    5′-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-3′,4′-dihydroxy-tetrahydrofuran-2′-ylmethyl    ester,-   Compound 5: (2′R,3′S,4′R,5′R)-5-[1,2]Dithiolan-3-yl-pentanoic acid    5′-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-3′,4′-dihydroxy-tetrahydrofuran-2′-ylmethyl    ester,-   Compound S5: (2′R,3S,3′S,4′R,5′R)-5-[1,2]Dithiolan-3-yl-pentanoic    acid    5′-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-3′,4′-dihydroxy-tetrahydrofuran-2′-ylmethyl    ester,-   Compound R5: (2′R,3R,3′S,4′R,5′R)-5-[1,2]Dithiolan-3-yl-pentanoic    acid    5′-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-3′,4′-dihydroxy-tetrahydrofuran-2′-ylmethyl    ester,-   Compound 5′: (2′R,3′S,4′R,5′R)-6,8-Dimercapto-octanoic acid    5′-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-3′,4′-dihydroxy-tetrahydrofuran-2′-ylmethyl    ester, and    pharmaceutically acceptable salts of these compounds.

The inventive compounds of the general formula (I) and/orpharmaceutically acceptable salts thereof are administered in a dosagecorresponding to an effective concentration in the range of 1-10000 mg,preferably in the range of 1-5000 mg, more preferably in the range of10-1000 mg, and most preferably in the range of 100-800 mg.

Another preferred embodiment of the present invention relates to thecombination of at least one compound of the general formula (I) and/orpharmaceutically acceptably salts thereof with further therapeuticdrugs, agents, or compounds. Said further therapeutic compounds areselected from the group comprising vitamins and anti-retroviral drugs.Suitable vitamins are vitamin A, B1, B2, B6, B12, C, E, andpharmaceutically acceptable salts thereof.

A further aspect of the present invention relates to a method forpreventing and/or treating diabetes mellitus Type I and Type II,inflammation, cancer, necrosis, gastric ulcers, neurodegenerativediseases (Alzheimer's disease, Parkinson's disease), neuropathicdiseases, neuropathic pain and polyneuropathy, peripheral and/or centralnerve diseases, degradation of the peripheral and/or central nervesystem, heavy metal poisoning, ishemic diseases and ishemic heartdisease, liver diseases and dysfunction of liver, allergies,cardiovascular diseases, Chlamydia pneumoniae, depression, obesity,stroke, pain, and retroviral infections (HIV, AIDS), includingopportunistic infections, in a mammal, including a human, whichcomprises administering to said mammal an amount of at least onecompound of the general formula (I) and/or pharmaceutically acceptablesalts thereof effective to treat the disease. Also disclosed is a methodfor stimulating the organism, especially specific organs and/or thecentral nervous system of a mammal, especially a human, comprising thestep of administering to said mammal an amount of at least one inventivecompounds and/or a salt thereof effective to stimulate body functions ofsaid mammal.

Preferably inventive uridine or deoxyuridine compounds are used withinsaid method wherein R″ represents dodecanyl, hexadecanyl, octadecanyl,eicosanyl, docosanyl, tetracosanyl, cis-9-tetradecenyl,cis-9-hexadecenyl, cis-6-octadecenyl, cis-9-octadecenyl,cis-11-octadecenyl, cis-9-eicosenyl, cis-11-eicosenyl, cis-13-docosenyl,cis-15-tetracosenyl, 9,12-octadecadienyl, 6,9,12-octadecatrienyl,8,11,14-eicosatrienyl, 5,8,11,14-eicosatetraenyl,7,10,13,16-docosatetraenyl, 4,7,10,13,16-docosapentaenyl,9,12,15-octadecatrienyl, 6,9,12,15-octadecatetraenyl,8,11,14,17-eicosatetraenyl, 5,8,11,14,17-eicosapentaenyl,7,10,13,16,19-docosapentaenyl, 4,7,10,13,16,19-docosahexaenyl,5,8,11-eicosatrienyl, 1,2-dithiolane-3-pentanyl, 6,8-dithiane octanyl,docosaheptadecanyl, eleostearyl, calendyl, catalpyl, taxoleyl,pinolenyl, sciadonyl, retinyl, 14-methyl pentadecanyl, pristanyl,phytanyl, 11,12-methyleneoctadecanyl, 9,10-methylenehexadecanyl,9,10-epoxystearyl, 9,10-epoxyoctadec-12-enyl, 6-octadecynyl,t11-octadecen-9-ynyl, 9-octadecynyl, 6-octadecen-9-ynyl,t10-heptadecen-8-ynyl, 9-octadecen-12-ynyl, t7,t11-octadecadiene-9-ynyl,t8,t10-octadecadiene-12-ynyl, 5,8,11,14-eicosatetraynyl,2-hydroxytetracosanyl, 2-hydroxy-15-tetracosenyl,12-hydroxy-9-octadecenyl, and 14-hydroxy-11-eicosenyl.

More preferred are these compounds wherein R″ represents9,12-octadecadienyl, 6,9,12-octadecatrienyl, 8,11,14-eicosatrienyl,5,8,11,14-eicosatetraenyl, 9,12,15-octadecatrienyl,6,9,12,15-octadecatetraenyl, 8,11,14,17-eicosatetraenyl,5,8,11,14,17-eicosapentaenyl, 7,10,13,16,19-docosapentaenyl,4,7,10,13,16,19-docosahexaenyl, 5,8,11-eicosatrienyl,1,2-dithiolane-3-pentanyl, and 6,8-dithiane octanyl.

Most preferred within said method are the following compounds:

-   Compound 1: (2′R,3′S,4′R,5′R)-Octadeca-6,9,12-trienoic acid    5′-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-3′,4′-dihydroxy-tetrahydrofuran-2′-ylmethyl    ester,-   Compound 2: (2′R,3′S,4′R,5′R)-Octadeca-9,12,15-trienoic acid    5′-(2,4-dioxo-3,4-dioxo-2H-pyrimidine-1-yl)-3′,4′-dihydroxy-tetrahydrofuran-2′-ylmethyl    ester,-   Compound 3: (2′R,3′S,4′R,5′R)-Icosa-5,8,11,14,17-pentaenoic acid    5′-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-3′,4′-dihydroxy-tetrahydrofuran-2′-ylmethyl    ester,-   Compound 4: (2′R,3′S,4′R,5′R)-Docosa-4,7,10,13,16,19-hexaenoic acid    5′-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-3′,4′-dihydroxy-tetrahydrofuran-2′-ylmethyl    ester,-   Compound 5: (2′R,3′S,4′R,5′R)-5-[1,2]Dithiolan-3-yl-pentanoic acid    5′-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-3′,4′-dihydroxy-tetrahydrofuran-2′-ylmethyl    ester,-   Compound S5: (2′R,3S,3′S,4′R,5′R)-5-[1,2]Dithiolan-3-yl-pentanoic    5′-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-3′,4′-dihydroxy-tetrahydrofuran-2′-ylmethyl    ester,-   Compound R5: (2′R,3R,3′S,4′R,5′R)-5-[1,2]Dithiolan-3-yl-pentanoic    acid    5′-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-3′,4′-dihydroxy-tetrahydrofuran-2′-ylmethyl    ester,-   Compound 5′: (2′R,3′S,4′R,5′R)-6,8-Dimercapto-octanoic acid    5′-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-3′,4′-dihydroxy-tetrahydrofuran-2′-ylmethyl    ester, and    pharmaceutically acceptable salts of these compounds.

Within said inventive method the compounds of the general formula (I)are administered in a dosage corresponding to an effective concentrationin the range of 1-10000 mg, preferably in the range of 1-5000 mg, morepreferably in the range of 10-1000 mg, and most preferably in the rangeof 100-800 mg.

Furthermore, administering at least one compound of the presentinvention and/or pharmaceutically acceptable salts thereof incombination with further therapeutic drugs, agents, or compounds is alsoadvantageous. Said further therapeutic compounds are selected from thegroup comprising vitamins and anti-retroviral drugs. Suitable vitaminsare vitamin A, B1, B2, B6, B12, C, E, and pharmaceutically acceptablesalts thereof.

A further aspect of the present invention is directed to pharmaceuticalcompositions comprising at least one compound of the general formula (I)and/or pharmaceutically acceptable salts thereof as an active ingredientand a pharmaceutically acceptable carrier, excipient, adjuvant and/ordiluents. Said pharmaceutical composition may further compriseadditional therapeutically active compounds which may be selected fromthe group comprising vitamins and anti-retroviral drugs. Especiallyvitamins like vitamin A, B1, B2, B6, B12, C, E, and pharmaceuticallyacceptable salts thereof can be further added.

The compounds of the general formula (I) and also the inventive drugcombinations can also be administered in form of their pharmaceuticallyactive salts optionally using substantially nontoxic pharmaceuticallyacceptable carrier, excipients, adjuvants or diluents. The medicationsof the present invention are prepared in a conventional solid or liquidcarrier or diluent and a conventional pharmaceutically-made adjuvant atsuitable dosage level in a known way. The preferred preparations andformulations are in administratable form which is suitable for oralapplication. These administratable forms, for example, include pills,tablets, film tablets, coated tablets, capsules, powders and deposits.Other than oral administratable forms are also possible. The inventiveuridine and deoxyuridine compounds or pharmaceutical preparations andformulations containing said compounds may be administered by anyappropriate means, including but not limited to injection (intravenous,intraperitoneal, intramuscular, subcutaneous) by absorption throughepithelial or mucocutaneous linings (oral mucosa, rectal and vaginalepithelial linings, nasopharyngial mucosa, intestinal mucosa); orally,rectally, transdermally, topically, intradermally, intragastrally,intracutaneously, intravaginally, intravasally, intranasally,intrabuccally, percutaneously, sublingually, or inhalation or any othermeans available within the pharmaceutical arts.

Within the disclosed methods the pharmaceutical compositions of thepresent invention, containing at least one inventive compound of thegeneral formula (I) or pharmaceutically acceptable salts thereof as anactive ingredient will typically be administered in admixture withsuitable carrier materials suitably selected with respect to theintended form of administration, i.e. oral tablets, capsules (eithersolid-filled, semi-solid filled or liquid filled), powders forconstitution, oral gels, elixirs, dispersible granules, syrups,suspensions, and the like, and consistent with conventionalpharmaceutical practices. For example, for oral administration in theform of tablets or capsules, the active ingredient may be combined withany oral nontoxic pharmaceutically acceptable inert carrier, such aslactose, starch, sucrose, cellulose, magnesium stearate, dicalciumphosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid forms)and the like. Moreover, when desired or needed, suitable binders,lubricants, disintegrating agents and coloring agents may also beincorporated in the mixture. Powders and tablets may be comprised offrom about 5 to about 95 percent inventive composition.

Suitable binders include starch, gelatin, natural sugars, cornsweeteners, natural and synthetic gums such as acacia, sodium alginate,carboxymethyl-cellulose, polyethylene glycol and waxes. Among thelubricants there may be mentioned for use in these dosage forms, boricacid, sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrants include starch, methylcellulose, guar gum and the like.Sweetening and flavoring agents and preservatives may also be includedwhere appropriate. Some of the terms noted above, namely disintegrants,diluents, lubricants, binders and the like, are discussed in more detailbelow.

Additionally, the compositions of the present invention may beformulated in sustained release form to provide the rate controlledrelease of any one or more of the components or active ingredients tooptimize the therapeutic effects. Suitable dosage forms for sustainedrelease include layered tablets containing layers of varyingdisintegration rates or controlled release polymeric matricesimpregnated with the active components and shaped in tablet form orcapsules containing such impregnated or encapsulated porous polymericmatrices.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injections or addition of sweeteners and opacifiers fororal solutions, suspensions and emulsions. Liquid form preparations mayalso include solutions for intranasal administration.

Aerosol preparations suitable for inhalation and intranasaladministration may include solutions and solids in powder form, whichmay be in combination with a pharmaceutically acceptable carrier such asinert compressed gas, e.g. nitrogen. Beside oral administration,inhalation is a preferred form for the application of the compounds ofthe present invention.

For preparing suppositories, a low melting wax such as a mixture offatty acid glycerides such as cocoa butter is first melted, and theactive ingredient is dispersed homogeneously therein by stirring orsimilar mixing. The molten homogeneous mixture is then poured intoconvenient sized molds, allowed to cool and thereby solidify.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The inventive uridine and deoxyuridine compounds of the presentinvention may also be deliverable transdermally. The transdermalcompositions may take the form of creams, lotions, aerosols and/oremulsions and can be included in a transdermal patch of the matrix orreservoir type as are conventional in the art for this purpose.

The term capsule refers to a special container or enclosure made ofmethyl cellulose, polyvinyl alcohols, or denatured gelatins or starchfor holding or containing compositions comprising the activeingredients. Hard shell capsules are typically made of blends ofrelatively high gel strength bone and pork skin gelatins. The capsuleitself may contain small amounts of dyes, opaquing agents, plasticizersand preservatives.

Tablet means compressed or molded solid dosage form containing theactive ingredients with suitable diluents. The tablet can be prepared bycompression of mixtures or granulations obtained by wet granulation, drygranulation or by compaction well known to a person skilled in the art.

Oral gels refers to the active ingredients dispersed or solubilized in ahydrophilic semi-solid matrix.

Powders for constitution refers to powder blends containing the activeingredients and suitable diluents which can be suspended in water orjuices.

Suitable diluents are substances that usually make up the major portionof the composition or dosage form. Suitable diluents include sugars suchas lactose, sucrose, mannitol and sorbitol, starches derived from wheat,corn rice and potato, and celluloses such as microcrystalline cellulose.The amount of diluent in the composition can range from about 5 to about95% by weight of the total composition, preferably from about 25 toabout 75%, more preferably from about 30 to about 60% by weight, andmost preferably from about 40 to 50% by weight.

The term disintegrants refers to materials added to the composition tohelp it break apart (disintegrate) and release the medicaments. Suitabledisintegrants include starches, “cold water soluble” modified starchessuch as sodium carboxymethyl starch, natural and synthetic gums such aslocust bean, karaya, guar, tragacanth and agar, cellulose derivativessuch as methylcellulose and sodium carboxymethylcellulose,microcrystalline celluloses and cross-linked microcrystalline cellulosessuch as sodium croscarmellose, alginates such as alginic acid and sodiumalginate, clays such as bentonites, and effervescent mixtures. Theamount of disintegrant in the composition can range from about 1 toabout 40% by weight of the composition, preferably 2 to about 30% byweight of the composition, more preferably from about 3 to 20% by weightof the composition, and most preferably from about 5 to about 10% byweight.

Binders characterize substances that bind or “glue” powders together andmake them cohesive by forming granules, thus serving as the “adhesive”in the formulation. Binders add cohesive strength already available inthe diluent or bulking agent. Suitable binders include sugars such assucrose, starches derived from wheat, corn rice and potato; natural gumssuch as acacia, gelatin and tragacanth; derivatives of seaweed such asalginic acid, sodium alginate and ammonium calcium alginate; cellulosicmaterials such as methylcellulose and sodium carboxymethylcellulose andhydroxypropyl-methylcellulose; polyvinylpyrrolidone; and inorganics suchas magnesium aluminum silicate. The amount of binder in the compositioncan range from about 1 to 30% by weight of the composition, preferablyfrom about 2 to about 20% by weight of the composition, more preferablyfrom about 3 to about 10% by weight, even more preferably from about 3to about 6% by weight.

Lubricant refers to a substance added to the dosage form to enable thetablet, granules, etc. after it has been compressed, to release from themold or die by reducing friction or wear. Suitable lubricants includemetallic stearates such as magnesium stearate, calcium stearate orpotassium stearate; stearic acid; high melting point waxes; and watersoluble lubricants such as sodium chloride, sodium benzoate, sodiumacetate, sodium oleate, polyethylene glycols and d'l-leucine. Lubricantsare usually added at the very last step before compression, since theymust be present on the surfaces of the granules and in between them andthe parts of the tablet press. The amount of lubricant in thecomposition can range from about 0.05 to about 15% by weight of thecomposition, preferably 0.2 to about 5% by weight of the composition,more preferably from about 0.3 to about 3%, and most preferably fromabout 0.3 to about 1.5% by weight of the composition.

Glidents are materials that prevent caking and improve the flowcharacteristics of granulations, so that flow is smooth and uniform.Suitable glidents include silicon dioxide and talc. The amount ofglident in the composition can range from about 0.01 to 10% by weight ofthe composition, preferably 0.1% to about 7% by weight of the totalcomposition, more preferably from about 0.2 to 5% by weight, and mostpreferably from about 0.5 to about 2% by weight.

Coloring agents are excipients that provide coloration to thecomposition or the dosage form. Such excipients can include food gradedyes and food grade dyes adsorbed onto a suitable adsorbent such as clayor aluminum oxide. The amount of the coloring agent can vary from about0.01 to 10% by weight of the composition, preferably from about 0.05 to6% by weight, more preferably from about 0.1 to about 4% by weight ofthe composition, and most preferably from about 0.1 to about 1%.

Techniques for the formulation and administration of the inventivecompounds of the present invention may be found in “Remington'sPharmaceutical Sciences” Mack Publishing Co., Easton Pa. A suitablecomposition comprising at least one compound of the invention and/orpharmaceutically acceptable salts thereof may be a solution of thecompound in a suitable liquid pharmaceutical carrier or any otherformulation such as tablets, pills, film tablets, coated tablets,dragees, capsules, powders and deposits, gels, syrups, slurries,suspensions, emulsions, and the like.

Toxicity and therapeutic efficacy of the inventive compounds may bedetermined by standard pharmaceutical, pharmacological, andtoxicological procedures in cell cultures or experimental animals fordetermining the LD50 (the dose lethal to 50% of the population) and theED50 (the dose therapeutically effective in 50% of the population). Thedose ratio between toxic and therapeutic effect is the therapeutic indexand can be expressed as the ratio between LD50 and ED50. The dosage ofthe compound lies preferably within a range of circulatingconcentrations that include the ED50 with little or no toxicity. Theactual amount of the composition administered will be dependent on thesubject being treated, on the subject's weight, the severity of thedisease, the manner of administration and the judgement of theprescribing physician.

Still a further aspect of the present invention relates to a drugcombination comprising at least one fatty acid and/or fatty acid alkylester selected from the group comprising linoleic acid, γ-linolenicacid, dihomo-γ-linolenic acid, arachidonic acid,7,10,13,16-docosatetraenoic acid, 4,7,10,13,16-docosapentaenoic acid,α-linolenic acid, stearidonic acid, 8,11,14,17-eicosatetraenoic acid,EPA, DPA, DHA, Mead acid, eleostearic acid, calendic acid, catalpicacid, stellaheptaenoic acid, taxoleic acid, pinolenic acid, sciadonicacid, retinoic acid, isopalmitic acid, pristanic acid, phytanic acid,11,12-methyleneoctadecanoic acid, 9,10-methylenehexadecanoic acid,coronaric acid, (R,S)-lipoic acid, (S)-lipoic acid, (R)-lipoic acid,(R,S)-6,8-dithiane octanoic acid, (R)-6,8-dithiane octanoic acid,(S)-6,8-dithiane octanoic acid, tariric acid, santalbic acid, stearolicacid, 6,9-octadecenynoic acid, pyrulic acid, crepenynic acid, heistericacid, t8,t10-octadecadiene-12-ynoic acid, ETYA, cerebronic acid,hydroxynervonic acid, ricinoleic acid, lesquerolic acid, brassylic acid,thapsic acid, and/or pharmaceutically acceptable salts thereof and/orlinoleic acid C1-C7 alkyl ester, γ-linolenic acid C1-C7 alkyl ester,dihomo-γ-linolenic acid C1-C7 alkyl ester, arachidonic acid C1-C7 alkylester, 7,10,13,16-docosatetraenoic acid C1-C7 alkyl ester,4,7,10,13,16-docosapentaenoic acid C1-C7 alkyl ester, α-linolenic acidC1-C7 alkyl ester, stearidonic acid C1-C7 alkyl ester,8,11,14,17-eicosatetraenoic acid C1-C7 alkyl ester, EPA C1-C7 alkylester, DPA C1-C7 alkyl ester, DHA C1-C7 alkyl ester, Mead acid C1-C7alkyl ester, eleostearic acid C1-C7 alkyl ester, calendic acid C1-C7alkyl ester, catalpic acid C1-C7 alkyl ester, stellaheptaenoic acidC1-C7 alkyl ester, taxoleic acid C1-C7 alkyl ester, pinolenic acid C1-C7alkyl ester, sciadonic acid C1-C7 alkyl ester, retinoic acid C1-C7 alkylester, isopalmitic acid C1-C7 alkyl ester, pristanic acid C1-C7 alkylester, phytanic acid C1-C7 alkyl ester, 11,12-methyleneoctadecanoic acidC1-C7 alkyl ester, 9,10-methylenehexadecanoic acid C1-C7 alkyl ester,coronaric acid C1-C7 alkyl ester, (R,S)-lipoic acid C1-C7 alkyl ester,(S)-lipoic acid C1-C7 alkyl ester, (R)-lipoic acid C1-C7 alkyl ester,(R,S)-6,8-dithiane octanoic acid C1-C7 alkyl ester, (R)-6,8-dithianeoctanoic acid C1-C7 alkyl ester, (S)-6,8-dithiane octanoic acid C1-C7alkyl ester, tariric acid C1-C7 alkyl ester, santalbic acid C1-C7 alkylester, stearolic acid C1-C7 alkyl ester, 6,9-octadecenynoic acid C1-C7alkyl ester, pyrulic acid C1-C7 alkyl ester, crepenynic acid C1-C7 alkylester, heisteric acid C1-C7 alkyl ester, t8,t10-octadecadiene-12-ynoicacid C1-C7 alkyl ester, ETYA C1-C7 alkyl ester, cerebronic acid C1-C7alkyl ester, hydroxynervonic acid C1-C7 alkyl ester, ricinoleic acidC1-C7 alkyl ester, lesquerolic acid C1-C7 alkyl ester, brassylic acidC1-C7 alkyl ester, thapsic acid C1-C7 alkyl ester, together with atleast one nucleoside and/or nucleotide compound selected from the groupcomprising uridine, deoxyuridine, uridine monophosphate, deoxyuridinemonophosphate, and/or pharmaceutically acceptable salts thereof.

Preferred is the combination of uridine, deoxyuridine, uridinemonophosphate, or deoxyuridine monophosphate with linoleic acid,γ-linolenic acid, dihomo-γ-linolenic acid, arachidonic acid,7,10,13,16-docosatetraenoic acid, 4,7,10,13,16-docosapentaenoic acid,α-linolenic acid, stearidonic acid, 8,11,14,17-eicosatetraenoic acid,EPA, DPA, DHA, Mead acid, (R,S)-lipoic acid, (S)-lipoic acid, (R)-lipoicacid, (R,S)-6,8-dithiane octanoic acid, (R)-6,8-dithiane octanoic acid,(S)-6,8-dithiane octanoic acid, eleostearic acid, catalpic acid,calendic acid, docosaheptadecanoic acid, taxoleic acid, pinolenic acid,sciadonic acid, retinoic acid and/or pharmaceutically acceptable saltsthereof, and/or linoleic acid C1-C7 alkyl ester, γ-linolenic acid C1-C7alkyl ester, dihomo-γ-linolenic acid C1-C7 alkyl ester, arachidonic acidC1-C7 alkyl ester, 7,10,13,16-docosatetraenoic acid C1-C7 alkyl ester,4,7,10,13,16-docosapentaenoic acid C1-C7 alkyl ester, α-linolenic acidC1-C7 alkyl ester, stearidonic acid C1-C7 alkyl ester,8,11,14,17-eicosatetraenoic acid C1-C7 alkyl ester, EPA C1-C7 alkylester, DPA C1-C7 alkyl ester, DHA C1-C7 alkyl ester, Mead acid C1-C7alkyl ester, (R,S)-lipoic acid C1-C7 alkyl ester, (S)-lipoic acid C1-C7alkyl ester, (R)-lipoic acid C1-C7 alkyl ester, (R,S)-6,8-dithianeoctanoic acid C1-C7 alkyl ester, (R)-6,8-dithiane octanoic acid C1-C7alkyl ester, (S)-6,8-dithiane octanoic acid C1-C7 alkyl ester,eleostearic acid C1-C7 alkyl ester, catalpic acid C1-C7 alkyl ester,calendic acid C1-C7 alkyl ester, docosaheptadecanoic acid C1-C7 alkylester, taxoleic acid C1-C7 alkyl ester, pinolenic acid C1-C7 alkylester, sciadonic acid C1-C7 alkyl ester, and/or retinoic acid C1-C7alkyl ester.

More preferred is a drug combination comprising uridine, deoxyuridine,uridine monophosphate, or deoxyuridine monophosphate with γ-linolenic,α-linolenic, EPA, DHA, (R,S)-6,8-dithiane octanoic acid,(R)-6,8-dithiane octanoic acid, (S)-6,8-dithiane octanoic acid,(R,S)-lipoic acid, (S)-lipoic acid, and/or (R)-lipoic acid, and/orpharmaceutically acceptable salts thereof, and/or γ-linolenic C1-C7alkyl ester, α-linolenic C1-C7 alkyl ester, EPA C1-C7 alkyl ester, DHAC1-C7 alkyl ester, (R,S)-6,8-dithiane octanoic acid C1-C7 alkyl ester,(R)-6,8-dithiane octanoic acid C1-C7 alkyl ester, (S)-6,8-dithianeoctanoic acid C1-C7 alkyl ester, (R,S)-lipoic acid C1-C7 alkyl ester,(S)-lipoic acid C1-C7 alkyl ester, and/or (R)-lipoic acid C1-C7 alkylester.

Most preferred is a drug combination of (R,S)-lipoic acid, (S)-lipoicacid, (R)-lipoic acid, (R,S)-6,8-dithiane octanoic acid,(R)-6,8-dithiane octanoic acid, and/or (S)-6,8-dithiane octanoic acid,and/or (R,S)-lipoic acid C1-C7 alkyl ester, (S)-lipoic acid C1-C7 alkylester, (R)-lipoic acid C1-C7 alkyl ester, (R,S)-6,8-dithiane octanoicacid C1-C7 alkyl ester, (R)-6,8-dithiane octanoic acid C1-C7 alkylester, and/or (S)-6,8-dithiane octanoic acid C1-C7 alkyl ester withuridine, deoxyuridine, uridine monophosphate, or deoxyuridinemonophosphate, and/or pharmaceutically acceptable salts thereof.

Suitable alcohols for the formation of the C1-C7 alkyl ester of theabove mentioned fatty acids are: methanol, ethanol, propanol,iso-propanol, butanol, sec-butanol, tert-butanol, iso-butanol, pentanol,iso-pentanol, cyclopentanol, hexanol, cyclohexanol, heptanol.

Said drug combination may further comprise suitable pharmaceuticallyacceptable carriers, excipients, adjuvant and/or diluents as describedabove in detail.

Another aspect of the present invention is related to the use of saiddrug combination for prophylaxis and/or treatment of diabetes mellitusType I and Type II inflammation, cancer, necrosis, gastric ulcers,neurodegenerative diseases (Alzheimer's disease, Parkinson's disease),neuropathic diseases, neuropathic pain and polyneuropathy, peripheraland/or central nerve diseases, degradation of the peripheral and/orcentral nerve system, heavy metal poisoning, ishemic diseases andishemic heart disease, liver diseases and dysfunction of liver,allergies, cardiovascular diseases, Chlamydia pneumoniae, depression,obesity, stroke, pain, and retroviral infections (HIV, AIDS), includingopportunistic infections. Furthermore, the drug combination comprisingat least one compound of the general formula (I) and/or pharmaceuticallyacceptable salts thereof can be used as stimulant drug, especially forthe treatment of attention-deficit disorder, narcolepsy, obesity,anxiety, depression, epilepsy, psychosis and sleeping disorders and tostimulate specific body functions, especially of the central nervoussystem.

Said drug combination may also be used for the manufacture of apharmaceutical formulation or preparation for prophylaxis and/ortreatment of diabetes mellitus Type I and Type II, inflammation, cancer,necrosis, gastric ulcers, neurodegenerative diseases (Alzheimer'sdisease, Parkinson's disease), neuropathic diseases, neuropathic painand polyneuropathy, peripheral and/or central nerve diseases,degradation of the peripheral and/or central nerve system, heavy metalpoisoning, ishemic diseases and ishemic heart disease, liver diseasesand dysfunction of liver, allergies, cardiovascular diseases, Chlamydiapneumoniae, depression, obesity, stroke, pain, and retroviral infections(HIV, AIDS), including opportunistic infections. Said pharmaceuticalformulation comprising the drug combination is also useful as stimulantin order to treat attention-deficit disorder, narcolepsy, obesity,anxiety, depression, epilepsy, psychosis and sleeping disorders and tostimulate specific body functions, especially of the central nervoussystem.

Said pharmaceutical formulation or preparation can be manufactured in aform suitable for intravenous, intraperitoneal, intramuscular,subcutaneous, oral, rectal, epithelial, intestinal, transdermal,topical, intradermal, intragastral, intracutan, intravaginal,intravasal, intranasal, intrabuccal, percutan, sublingual, or any otherapplication. Furthermore, said pharmaceutical formulation may alsocomprise at least one substantially nontoxic pharmaceutically acceptablecarrier, excipients, adjuvants or diluents as described above in detail.

The inventive drug combination is administered in a dosage correspondingto an effective concentration in the range of 1-15000 mg, preferably1-8000 mg, more preferably 1-5000 mg, even more preferably in the rangeof 10-2000 mg, and most preferably in the range of 100-1000 mg.

Another advantageous aspect of the present invention is directed to saiddrug combination which further comprises another therapeutic agent orcompound wherein said further therapeutic compound is selected from thegroup comprising vitamins and anti-retroviral drugs. Suitable vitaminsare vitamin A, B1, B2, B6, B12, C, E, and pharmaceutically acceptablesalts thereof.

Also revealed for the first time is a method for preventing and/ortreating diabetes mellitus Type I and Type II, inflammation, cancer,necrosis, gastric ulcers, neurodegenerative diseases (Alzheimer'sdisease, Parkinson's disease), neuropathic diseases, neuropathic painand polyneuropathy, peripheral and/or central nerve diseases,degradation of the peripheral and/or central nerve system, heavy metalpoisoning, ishemic diseases and ishemic heart disease, liver diseasesand dysfunction of liver, allergies, cardiovascular diseases, Chlamydiapneumoniae, depression, obesity, stroke, pain, and retroviral infections(HIV, AIDS), including opportunistic infections, in a mammal, includinga human, which comprises administering to said mammal an amount of saiddrug combination effective to treat said disease or dysfunction. Inaddition thereto, a method for stimulating the organism and specificbody functions of said mammal is disclosed comprising administering tosaid mammal an amount of said drug combination effective to stimulatethe organism and said specific body functions.

Within said inventive method the drug combination is administered in adosage corresponding to an effective concentration in the range of1-30000 mg, preferably in the range of 10-20000 mg, more preferably inthe range of 50-15000 mg, even more preferably in the range of 100-10000mg, and most preferably in the range of 1000-6000 mg.

DESCRIPTION OF THE FIGURES

FIGS. 1 a, 1 b and 1 c show a group of selected fatty acids;

FIG. 2 shows ribose, deoxyribose and the nucleosides uracil, cytosine,and thymine, the basic residues of the compounds of the general formula(I);

FIG. 3 discloses the structures of six highly active compounds of thegeneral formula (I):

-   Compound 1: (2′R,3′S,4′R,5′R)-Octadeca-6,9,12-trienoic acid    5′-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-3′,4′-dihydroxy-tetrahydrofuran-2′-ylmethyl    ester,-   Compound 2: (2′R,3′S,4′R,5′R)-Octadeca-9,12,15-trienoic acid    5′-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-3′,4′-dihydroxy-tetrahydrofuran-2′-ylmethyl    ester,-   Compound 3: (2′R,3′S,4′R,5′R)-Icosa-5,8,11,14,17-pentaenoic acid    5′-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-3′,4′-dihydroxy-tetrahydrofuran-2′-ylmethyl    ester,-   Compound 4: (2′R,3′S,4′R,5′R)-Docosa-4,7,10,13,16,19-hexaenoic acid    5′-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-3′,4′-dihydroxy-tetrahydrofuran-2′-ylmethyl    ester,-   Compound 5: (2′R,3′S,4′R,5′R)-5-[1,2]Dithiolan-3-yl-pentanoic acid    5′-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-3′,4′-dihydroxy-tetrahydrofuran-2′-ylmethyl    ester, and-   Compound 5′: (2′R,3′S,4′R,5′R)-6,8-Dimercapto-octanoic acid    5′-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-3′,4′-dihydroxy-tetrahydrofuran-2′-ylmethyl    ester.

FIG. 4 shows the effect of compound 5′ on the dopamine concentration inrat striatum. The harmful malonate-induced dopamine depletion in ratstriatum can almost be compensated by the administration of relativelylow concentrations of compound 5′;

FIG. 5 a shows that compound 5′ is able to significantly increase the5-HT concentration in rat substantia nigra;

FIG. 5 b shows that compound 5′ is able to significantly increase the5-HIAA level in rat substantia nigra.

EXAMPLES Example 1 General Procedure for Esterification

1 mol equivalent of fatty acid was dissolved in a polar aprotic solvent.Preferred solvents are dichloromethane, chloroform, or ethers such asTHF. 0.1-2.0 mol equivalents, preferably 0.5 to 1.2 mol equivalents, ofdicyclohexylcarbodiimide (DCC) preferably dissolved in the reactionsolvent were added in one portion. After a couple of minutes 1.0 molequivalent of a protected nucleoside or deoxynucleosid were given to thesolution and after another couple of minutes catalytic or semi-equimolaramounts of dimethyl aminopyridine (DMAP) were added. The reactionmixture was stirred for 10 to 20 hours under exclusion of light.Purification of the obtained products were performed according tostandard procedures well known in the state of the art.

Example 2 General Procedure for Ketal Cleavage

The cleavage of ketals is performed under acidic conditions. Forexample, benzylsulfonic acids or other organic acids dissolved inorganic solvents may be used. The best results were obtained with aceticacid and most preferably with 80% acetic acid. The reaction was normallycarried out at elevated temperature, preferably between 80° C. and 100°C. for several hours, preferably 2 to 6 hours depending on the stabilityof the reactants. After neutralization the purification of the compoundaccording to general formula (I) were performed according to standardprocedures well known to a skilled person.

Example 3 Synthesis of Compound 3

Step 1: Esterification

2.00 g (6.61 mmol) EPA were dissolved under nitrogen in 10 mldichloromethane. 1.38 g (1.16 mmol) DCC dissolved in 20 mldichloromethane were added and after 5 minutes 1.88 g (6.61 mmol) ketalprotected uridine as obtained from step 1 according to example 5 wereadded. After another 5 minutes 25 mg DMAP were given to the solution.The reaction was stirred over night at room temperature in the dark. Theresulting solution was diluted with 30 ml MTBE (methyl tert-butylether), filtered, and concentrated. The brown and oily remainder waspurified by column chromatography using hexane : isopropanol (5:1) aseluent. A colorless oil was obtained.

Yield: 3.42 g (6.01 mmol, 91% th.)

Step 2: Ketal Cleavage

3.10 g (5.45 mmol) ketal protected compound 3 as obtained from step 1were dissolved in 40 ml 80% acetic acid and heated up to approximately95° C. for 4.5 hours. The acetic acid was removed under reduced pressureand the remainder was redissloved in 50 ml ethyl acetate, washed withsaturated NaHCO₃ solution, twice with brine, dried over Na₂SO₄, andconcentrated. A brown oil was obtained which was purified by columnchromatography using dichloromethane: methanol (10:1) as eluent. A lightyellow and highly viscous oil was obtained.

Yield: 1.52 g (2.88 mmol, 53% th.)

Compound 3:

MS (m/z(%)): 528 (2,37) M⁺; 113 (100)

¹H-NMR (400 MHz; CDCl₃): δ=0.98 (t, 3H), 1.69-1.76 (m, 2H), 2.05-2.16(m, 4H), 2.35-2.39 (m, 2H), 2.79-2.87 (m, 8H), 4.12-4.14 (m, 1H),4.25-4.32 (m, 2H), 4.35-4.44 (m, 2H), 5.28-5.46 (m, 10H), 5.75 (d, 1H),5.82 (d, 1H), 7.62 (d, 1H), 10.15 (s, 1H)

¹³C-NMR (100.6 MHz; CDCl₃): δ=14.24, 20.54, 24.67, 24.82, 25.55, 25.63,26.45, 32.12, 33.45, 63.20, 70.22, 75.01, 82.23, 91.27, 102.48, 127.03,127.89, 128.05, 128.34, 128.57, 128.61, 128.72, 128.76, 129.24, 132.05,139.71, 151.18, 163.63, 173.92

Compounds 1 and 2 have been synthesized according to the above-mentionedprocedure wherein EPA was replaced either by γ-linolenic acid orα-linolenic acid. Yields are over 90% for step 1 and about 50% for step2.

Example 4 Synthesis of Compound 4

Step 1: Esterification

2.20 g (6.70 mmol) DHA were dissolved under nitrogen in 20 mldichloromethane. 1.40 g (6.78 mmol) DCC dissolved in 20 mldichloromethane were added and after 5 minutes 1.90 g (6.69 mmol) ketalprotected uridine as obtained from step 1 according to example 5 wereadded. After another 5 minutes 40 mg DMAP were given to the solution.The reaction was carried out under exclusion of light. The resultingsolution was diluted with 20 ml MTBE, filtered, washed with 10 ml MTBEand concentrated. The remainder was purified by column chromatographyusing hexane:ethyl acetate (2:1) as eluent. A colorless oil wasobtained.

Yield: 3.15 g (5.30 mmol, 79% th.)

Step 2: Ketal Cleavage

3.10 g (5.21 mmol) ketal protected compound 4 as obtained from step 1were dissolved in 125 ml 80% acetic acid and heated up to approximately95° C. The reaction was detected by TLC or HPLC. After two hours at 95°C. about 90% of the starting material was converted to compound 4. Theacetic acid was removed under reduced pressure and the remainder wasredissloved in 20 ml ethyl acetate, washed with saturated NaHCO₃solution, twice with brine, dried over Na₂SO₄, and concentrated. A brownoil was obtained which was purified by column chromatography usingdichloromethane:isopropanol (10:1) as eluent. A light yellow and highlyviscous oil was obtained.

Yield: 1.20 g (2.17 mmol, 42% th.)

Compound 4:

MS (m/z(%)): 555 (2,37) M⁺; 113 (100)

¹H-NMR (400 MHz; CDCl₃): δ=0.98 (t, 3H), 2.05-2.12 (m, 2H), 2.40-2.45(m, 4H), 2.80-2.89 (m, 1H), 3.52 (d, 1H), 4.13-4.16 (m, 1H), 4.25-4.32(m, 2H), 4.36-4.44 (m, 2H), 5.15 (d, 1H), 5.29-5.47 (m, 12H), 5.75 (d,1H), 5.82 (d, 1H), 7.62 (d, 1H), 10.10 (s, 1H)

¹³C-NMR (100.6 MHz; CDCl₃): δ=14.24, 20.55, 22.12, 22.62, 25.32, 25.55,25.61, 25.65, 34.00, 63.24, 70.23, 75.04, 82.26, 91.13, 102.47, 127.03,127.40, 127.88, 128.05, 128.07, 128.33, 128.49, 128.60, 129.86, 132.05,139.67, 151.19, 163.56, 172.61

Example 5 Synthesis of Compound 5

Step 1: Ketalization

27.7 g uridine were dissolved under nitrogen in 250 ml anhydrous acetoneand 11.8 g 2,2-dimethoxypropane. After addition of 0.3 ml conc. sulfuricacid the reaction mixture was stirred for about 20 h at roomtemperature. During this time a voluminous fine precipitation wasformed. After filtration the remaining solution was treated with 2 mltriethylamine in 80 ml dichlormethane and was subsequently washedthoroughly.

Yield: 21.9 g (77.0 mmol, 68% th)

Melting point: 159-160° C.

The yield can be further increased by reducing the volume of acetone forabout one third, and by adding heptane as an anti-solvent, and bycooling the mixture to 0-5° C. prior to filtration. Yields in the rangeof 80-85% can be obtained.

Because of cost reasons it has been demonstrated that the anhydrousacetone can be replaced by bulk acetone having a water content of 0.1%(w/w) without showing an effect on the yield.

Step 2: Esterification

4.00 g DL-α-lipoic acid were dissolved under nitrogen in 50 mldichlormethane and 4.00 g DCC (dicyclohexylcarbodiimide) dissolved in 70ml dichlormethane were added. After 5 minutes 5.51 g of the ketal asobtained from step 1 were given to the solution and after another 5minutes 150 mg DMAP (dimethylaminopyridine) were added. The solution wasstirred over night at room temperature, diluted with 100 ml MTBE (methyltert-butyl ether) and filtered. The solvent was removed under vacuum andthe remaining oil was purified by column chromatography on silica usinghexane:ethyl acetate (1:2) as eluent. A yellow viscous oil was obtained.

Yield: 8.06 g (17.1 mmol, 88% th)

The step 2 reaction can also be carried out in ethyl acetate having theadvantage that the reaction product can without purification directlysubjected to the reaction conditions of step 3. After stirring thereaction over night at room temperature the slight excess of DCC ishydrolysed to DCU (dicyclohexyl urea) by an aqueous 10% citric acid washand the excess of DL-α-lipoic acid is easily removed by washing with anaqueous NaHCO₃-solution. The DCU is removed during work-up byfiltration. Yields are between 50 and 90% th depending on scale andsolvent.

Beside DCC/DMAP also pivaloyl chloride/DMAP has been examined aseffective coupling agents. Solvents like toluene or ethers such as THFor dioxane can be used instead of dichloromethane. Instead of DCCN,N′-carbonyl diimidazole or chloroformic acid isobutyl ester may beused.

Step 3: Deprotection

11.7 g ketal protected compound 5 as obtained from step 2 were stirred5.5 h in 300 ml acetic acid at a temperature of about 95° C. Thereafter,the acetic acid was removed under vacuum and the remainder wasredissolved in 150 ml ethyl acetate. Said solution was washed two timeswith 70 ml saturated NaHCO₃-solution each and subsequently two timeswith 100 ml saturated NaCl-solution each. The solution was dried overNa₂SO₄ and the solvent was nearly removed completely (the concentrationto dryness should be avoided). The pale remainder was redissolved in 150ml ethyl acetate and optionally treated with ultrasonic for 2 -3 minuteswhile a yellow precipitate was formed. The precipitate (compound 5) wasseparated by filtration, washed with ethyl acetate and dried. Besideethyl acetate, n-BuOH, toluene, 1-pentanol, acetonitril or mixtures ofthese solvents have been examined as alternative precipitation solvents.

Yield: 7.42 g (17.2 mmol, 69% th)

Compound 5:

Melting point: 95-97° C.

Purity: >98% (HPLC)

MS (m/z(%)): 432 (7.9) M⁺, 113 (100)

¹H-NMR (400 MHz, d₄-methanol): δ=1.41-1.50 (m, 2H), 1.57-1.72 (m, 4H),1.82-1.90 (m, 1H), 2.37-2.47 (m, 3H), 3.04-3.18 (m, 2H), 3.51-3.57 (m,1H), 4.06-4.19 (m, 3H), 4.29-4.37 (m, 2H), 5.71 (d, 1H), 5.80 (d, 1H),7.66 (d, 1H).

¹³C-NMR (100.6 MHz, d₄-methanol): δ=25.7, 29.7, 34.7, 35.7, 39.3, 41.3,57.5, 64.6, 71.2, 75.2, 82.9, 91.8, 102.9, 142.3, 152.2, 166.0, 174.8

Example 6 Synthesis of compound S-5

Compound S-5 was synthesized according to the reaction procedures asoutlined in example 5. Instead of DL-α-lipoic acid the enantiomericallypure S-α-lipoic acid was used.

Compound S-5:

Melting point: 109-110° C.

¹H-NMR (400 MHz, d₆-DMSO): δ=1.30-1.40 (m, 2H), 1.47-1.56 (m, 3H),1.59-1.68 (m, 1H), 1.77-1.87 (m, 1H), 2.30-2.40 (m, 3H), 3.04-3.18 (m,2H), 3.53-3.60 (m, 1H), 3.88-3.97 (m, 2H), 4.02-4.06 (m, 1H), 4.13-4.23(m, 2H), 5.21 (d, 1H), 5.40 (d, 1H), 5.62 (d, 1H), 5.71 (d, 1H), 7.57(d, 1H).

Example 7 Synthesis of Compound R-5

Compound R-5 was synthesized according to the reaction procedures asoutlined in example 5. Instead of DL-α-lipoic acid the enantiomericallypure R-αlipoic acid was used.

Compound R-5:

Melting point: 88-89° C.

¹H-NMR (400 MHz, d₆-DMSO): δ=1.30-1.40 (m, 2H), 1.47-1.56 (m, 3H),1.59-1.68 (m, 1H), 1.79-1.86 (m,1H), 2.30-2.41 (m, 3H), 3.04-3.17 (m,2H), 3.53-3.60 (m, 1H), 3.88-3.97 (m, 2H), 4.02-4.06 (m, 1H), 4.13-4.24(m, 2H), 5.21 (d, 1H), 5.40 (d, 1H), 5.62 (d, 1H), 5.71 (d, 1H), 7.58(d, 1H), 11.27 (s, 1H).

Example 8 Synthesis of Compound 5′

2.28 g (5.27 mmol) of compound 5 were dissolved in 40 ml methanol underan inert atmosphere. The solution was cooled to 0° C. and 2.50 g (66.1mmol) sodium borhydride was added over 15 minutes in small portions.During NaBH₄ addition the yellow solution became colourless. Aftercomplete addition of sodium borhydride the solution was stirred for 45minutes, diluted with 50 ml water and acidified with concentrated HCl topH=1.50 ml chloroform were added and the organic layer was separated,washed twice with 10 ml brine, dried over Na₂SO₄ and concentrated. Afterpurification compound 5′ was obtained as colorless oil.

Yield: 1.63 g (3.75 mmol, 71% th.)

Compound 5:

MS (m/z(%)): 401 (18.0) M⁺-H₂S; 113 (100)

¹H-NMR (400 MHz, d₆-DMSO): δ=1.30-1.79 (m, 7H), 1.32-1.43 (m, 2H),1.85-1.94 (m, 1H), 2.33-2.40 (m, 2H), 2.61-2.76 (m, 2H), 2.88-2.96 (m,1H), 4.15 (s, br., 1H), 4.26 (s, br., 2H), 4.32-4.42 (m, 2H), 5.75 (d,1H), 5.83 (d, 1H), 7.58 (d, 1H), 10.32 (s, br., 1H).

¹³C-NMR (100.6 MHz, d₆-DMSO): δ=25.7, 29.7, 34.7, 35.7, 39.3, 41.3,57.5, 64.6, 71.2, 75.2, 82.9, 91.8, 102.9, 142.3, 152.2, 166.0, 174.8

Example 9 Diabetes and Polyneuropathy

The model used to determine the effect of the compounds of the presentinvention on treating diabetes and/or polyneuropathy comprises the useof in-vitro Hippocampus cuts for detecting the over-sensitiveness ofpyramid cells due to the enhancement of the glucose concentration. Saidover-sensitiveness could be antagonized dose-dependent by the use of acompound of the general formula (I).

The Hippocampus cuts of rats present a validated model for determinationof interaction between a drug substance which is in direct contact withneuronal tissue. The interaction between a pharmaceutically activecompound and the brain tissue can be examined directly, because of themaintenance of the three dimensional structure of the tissue within thein-vitro Hippocampus cut. Said compounds act on a special population ofnerve cells, the pyramid cells of the Hippocampus. It is known that thesynapse between pyramid cells and Schaffer-collaterals (which can beelectrically stimulated) use the neurotransmitter glutamate for theprocess of signal transduction. The result of the electric stimulation,the so called population spike, represents the amount of activatedpyramid cells. Other known models allow the in-vitro determination of aneuronal network only within a time frame of up to 8 hours. Theadvantage of this model is that neuronal network can be analyzedin-vitro over a much longer period after chemical or electricprovocation of the cells. The cells are brought to an elevated level ofstimulation which allows a long term measurement of pharmacologicallyactive compounds under patho-physiologic conditions (W. Dimpfel et al.,Antimicrobial Agents and Chemotherapy 1991, 1142-1146; W. Dimpfel etal., Eur. J. Med. Res. 1996, 1, 523-527).

Materials & Methods

Within the present method the level of stimulation was elevated by theuse of an increased concentration of glucose in the superfusion mediumin order to measure the antagonistic effect of the compounds of thepresent invention. Because of the fact that α-lipoic acid had beenapplied to this method (W. Dimpfel et al., Eur. J. Med. Res. 1996, 1,523-527), compound 5′ was selected as a close related compound in orderto produce reasonable results when comparing α-lipoic acid and uridinewith compound 5′. Thus, α-lipoic acid and uridine were selected asreference.

21 adult male CD rats had been used within the present studies. TheHippocampus was isolated after anesthetization and exsanguination of thetest animals. The middle part of the Hippocampus was fixed by means of aglue in phosphate-buffered saline (NaCl: 124 mM, KCl: 5 mM, CaCl₂: 2 mM,MgSO_(4: 2) mM, NaH₂PO₄: 1.25 mM, NaHCO₃: 26 mM, glucose: 10 mM; controlsolution: ACSF; Carl Roth, Karlsruhe, Germany). The Hippocampus wassubsequent cut into slides of 400 μM by means of a Vibratom (RhemaLabortechnik). The Hippocampus cuts were stored at least one hour beforethe test runs in an incubation chamber under carbogen (S. J. Schiff, G.G. Somjen, Brain Research 1985, 345, 279-284).

The experiment was carried out in a so called “Base Unit with Haas Top”(Medical Systems Corporation, U.S.A.) at a temperature of 35° C.according to the protocol of H. L. Haas and R. W. Greene(Neurotransmitter and cortical function; ed. M. Avoli, T. A. Reader, R.W. Dykes and P. Gloor, pp. 483-494, Plenum Publishing Corp.). TheHippocampus cut was placed on a piece of gauze and perfused by means ofperistaltic pumps. The test apparatus was flushed with carbogen (flowrate: 200 ml per hour) in order to maintain the necessary oxygen supply.

The CA₂-region was stimulated by means of a stimulus generator(laboratory computer, Pro Science) and a bipolar concentric steelelectrode (Rhodes Medical Systems, U.S.A.). A pulse width of 200 μs wasused and the amperage was constantly kept at 200 μA. The stimulusgenerator released four single stimulation signals within intervals of20 seconds which released a total number of four population spikes inthe Hippocampus cut. An average value of the four amplitudes of thespikes was calculated.

Results

The previous findings that α-lipoic acid is able to antagonize theover-senstiveness induced by an increased glucose concentration could bereproduced (W. Dimpfel et al., Eur. J. Med. Res. 1996, 1, 523-527).Furthermore, uridine was used as a second reference. The electric replyof the hippocampal pyramid cells in form of the population spike wasincreased for about 160% during the presence of 30 mM glucose comparedto the initial value of approximately 1 mV. All three substances,α-lipoic acid, uridine and compound 5′, were able to reducedose-dependent the elevated stimulation level.

It could be demonstrated that compound 5′ was active within a range of1-25 μM while said rang of concentration was extended to about 100 μMfor uridine. α-Lipoic acid shown a nearly linear effect up to aconcentration of 400 μM. Thus, the calculated IC₅₀-values for compound5′ are 5 μM, for uridine 40 μM, and for α-lipoic acid is the IC₅₀-valueapproximately 200 μM.

A direct comparison of the effect of compound 5′ with α-lipoic acid anduridine on the enhancement of the glucose-induced over-sensitivenesscould be performed by the use of the above described model. The elevatedlevel of over-sensitiveness of the hippocampal pyramid cells could bemost effectively treated with compound 5′ while uridine and α-lipoicacid showed only weaker effects.

Thus, it can be stressed that compound 5′ is able to significantlyreduce the increased over-sensitiveness and, therefore, the compoundsaccording to general formula (I) can be used as pharmaceuticallyeffective agents to treat diabetes and polyneuropathy.

Example 10 Diabetes and Polyneuropathy

According to the procedure and the model as outlined in Example 9 alsoS-5 and R-5 were tested and the test results were compared to those ofuridine and α-lipoic acid.

As a reply to the electric stimulation the population spike of theactivated pyramid cells was measured. The amplitude of the populationspike represents the amount of activated pyramid cells. The electricreply of the hippocampal pyramid cells in form of the population spikewas increased for about 160% to 170% during the presence of 30 mMglucose compared to the initial value of approximately 1 mV. Theamplitude of the population spike was measured in μV and the mean wascalculated of at least three measured amplitudes.

It could be demonstrated that compound R-5 was active within a range of1-15 μM while compound S-5 was active within the range of 1-10 μM. Asdescribed above, uridine showed activity within the concentration rangeof 1-100 μM and α-lipoic acid showed a nearly linear effect up to aconcentration of 400 μM. The calculated IC₅₀-value for compound S-5 is 4μM, for R-5 8 μM, for uridine 40 μM, and for α-lipoic acid is theIC₅₀-value approximately 200 μM.

A comparison of the effect of compounds 5′, S-5, and R-5 withIC₅₀-values within the range of 4-8 μM with α-lipoic acid(IC₅₀-value≈200 μM) and uridine (IC₅₀-value≈40 μM) on the enhancement ofthe glucose-induced over-sensitiveness could be performed by the use ofthe above described model. Said comparison proves that the compounds ofthe present invention are capable of reducing the elevated level ofover-sensitiveness of the hippocampal pyramid cells in a very similarmanner while uridine and α-lipoic acid showed much weaker effects.

Thus, it can be stated that the compounds of the present invention areable to significantly reduce the increased over-sensitiveness of thepyramid cells and, therefore, are pharmaceutically effective agents totreat diabetes and polyneuropathy.

Example 11 Neuroprotective Effects

As demonstrated by this example, the compounds of the present inventionshow neuroprotective potency. The neuroprotective effects of α-lipoicacid and more pronounced of dihydrolipoic acid are well known (P. Wolz,J. Krieglstein, Lipoic Acid in Health and Disease, New York, Basel, HongKong, Marcel Dekker Inc., 1997, pp. 205-225). Thus, dihydrolipoic acidwas chosen as a positive control for comparison reasons. The mostsimilar compound to dihydrolipoic acid of the present invention iscompound 5′. The mouse model as described below was used in order toexamine the dose-dependent neuroprotective effect of compound 5′ incomparison with dihydrolipoic acid and with untreated mice, i.e. micetreated only with a vehicle but without any active ingredient.

Materials & Methods

Permanent Focal Cerebral Ischemia in Mice:

Permanent middle cerebral artery (MCA) occlusion was performed in maleNMRI mice (12 to 17 animals per group) according to the method describedby Welsh et al. (J. Neurochem. 1987, 846-851). Briefly, after the micewere anesthetized with tribromoethanol (600 mg/kg intraperitoneally), asmall hole was drilled in the skull to expose the middle cerebralartery. The stem of the middle cerebral artery and both branches werepermanently occluded by electrocoagulation. Body temperature wasmaintained at 37° C.±1° C. with a heating lamp during the surgicalprocedure. Afterwards, the mice were kept at an environmentaltemperature of 30° C. for 2 hours after MCA occlusion.

For histologic evaluation, the mice were anesthetized again withtribromoethanol and perfused intraperitoneally with a 1.5% solution ofneutral red (0.5 ml) 2 days after middle cerebral artery occlusion. Thebrains were removed and stored in a fixative (4% formalin in phosphatebuffer solution, pH 7.4) for 24 hours.

In this model of focal cerebral ischemia in mice, only cortical tissuewas found to be infarcted, and furthermore, the infarct volumecorrelates with the infarct surface (C. Backhauβ et al., J. Pharmacol.Methods 1992, 27, 27-32). The tissue on the brain surface unstained byneutral red was determined (in square millimeters) as infarcted surfacearea by means of an image analyzing system (Kontron, Eching, Germany)according to the publication of C. Backhauβ.

The injection of compound 5′, dihydrolipoic acid, and the vehicle onlywas performed intraperitoneally 1 hour before MCA occlusion. Compound 5′and dihydrolipoic acid were dissolved in 25% macrogol 400 (vehicle). Theinjected volume was always 0.25-0.30 ml per mouse. Doses of 100, 150,and 500 mg/kg compound 5′ and 150 mg/kg dihydrolipoic acid were used.The control group received the vehicle (0.25-0.30 ml 25% macrogol 400per mouse) only.

Results

The results are given as means±SD (standard deviation). The differencesbetween compound 5′-treated, dihydrolipoic acid-treated, andvehicle-treated animals were evaluated statistically according to theANOVA and DUNCAN test.

In the first series of experiments it could be demonstrated thatcompound 5′ significantly reduced the infarcted area on the mouse brainsurface when administered in a concentration of 100 mg in 0.25-0.30 mlvehicle (cf. Table 6).

TABLE 6 Influence of comp. 5′ and dihydrolipoic acid on infarct areaafter permanent MCA occlusion in NMRI mice Compound Mean SD 0.25-0.30 mlvehicle only 29.89 ±2.59 100 mg/kg comp. 5′ 26.22 ±4.75 150 mg/kg comp.5′ 27.00 ±3.50 500 mg/kg comp. 5′ 28.24 ±4.12 150 mg/kg dihydrolipoicacid 27.94 ±3.02

This effect is not clearly dose-dependent, because it seems to decreasewith increasing dosage of compound 5′. Thus, it is predicted thatsomewhere between 20 mg/kg-100 mg/kg of compound 5′ per mouse a maximumneuroprotective effect is reached. This result shows that low dosages ofa compound of the present invention may be used to achieve a significantreduce of infarcted brain area.

The mean of the infarct area obtained from mice treated with 500 mg/kgcompound 5′ was no longer statistically reduced compared with thecontrols. The effect of the lowest dose of compound 5′ seemed to be themost pronounced and a decrease of the neuroprotective effect wasobserved at higher concentrations of compound 5′. At a concentration of500 mg/kg of compound 5′ only a slight neuroprotective effect wasdetected while dihydrolipoic acid showed no effect at all and did notreduce the infarct area in this study.

The results discussed above clearly demonstrate the neuroprotectiveeffect of compound 5′. In addition, the advantageous finding that amaximum neuroprotective effect is obtained at low concentrations isdescribed. Thus, it has been proven that the compounds of the presentinvention can be used as anti-ischemic drugs in order to treat, forinstance, stroke. Furthermore, no toxic effects could be detected inmice applied to the above-mentioned method.

Example 12 Neuroprotective Effects

This example was selected to determine the effect of the compounds ofthe present invention on the concentration of dopamine its metabolite3,4-dihydroxyphenyl acetic acid (DOPAC) and 5-hydroxytryptamine (5-HT orSerotonin) and its metabolite 5-hydroxyindol acetic acid (5-HIAA) in thesubstantia nigra and the Striatum of Wistar rats (Charles River,Sulzbach Rosenberg).

Said two brain regions were selected in order to examine dopaminergicneurons, because it is well known that said neurons are sensitive toneurotoxines which may cause M. Parkinson, Alzheimer, and ChoreaHuntington. The method as described below was used to determinedegenerative processes. Sodium malonate was used as a neurotoxicsubstance within said method.

Materials & Methods

It is known that sodium malonate increases the release von dopamine inthe Striatum of the test animals. Groups of six Wistar rats each havebeen used as test animals. Thus, the dopamine concentration can be usedas an indicator in order to determine the harmful effect ofneurotoxines.

100 mg of compound 5′ were dissolved in 5 ml 50% propan-1,2-diol (Merck,Darmstadt). Four 5 ml portions of compound 5′ were administeredintraperitoneal to the test animals. The first portion was administeredin the evening of the first test day, the second portion during the nextmorning, the third portion in the evening of the second test day and thelate portion during the morning of the third test day. Thirty minutesafter the last application of compound 5′ 2 μmol sodium malonatedissolved in physiologic sodium chloride solution were injected into theleft Striatum by means of a precision pump (flow rate 0.5 μl/min.) afterhaving anesthetized the rats (Ketamin: 80 mg/kg and Xylasin: 6-10mg/kg).

Four days after sodium malonate application, the Striatum and thetreated and untreated part of the substantia nigra was separatelyexcised, weighted, homogenized with perchloric acid, and centrifuged.Aliquots of the supernatants were subsequently subjected to HPLC and bythe means of HPLC-ELCD the amount of dopamine, DOPAC, 5-HT, 5-HIM, and3-methoxytyramine was colorimetrically measured.

Results

The application of sodium malonate leads to a reduction of dopamine andits metabolites HVA and DOPAC. The neurotoxin malonate decreased theconcentration of dopamine (−44%, p<0.001) and of DOPAC (−30%, p<0.001).Compound 5′ is able to increase the concentration of dopamine (+18%,p<0.05) and of DOPAC (+10%, p<0.05) in the Striatum. Furthermore, itcould be demonstrated that the application of malonate together withcompound 5′ did not lead to such a dramatic decrease in dopamine andDOPAC concentration. The additional application of compound 5′compensated the malonate effect (+44% more dopamine in comparison to theapplication of malonate only) (cf. FIG. 4).

Furthermore, it could be shown that administration of the compound 5′increased dramatically the level of 5-HT and its metabolite 5-HIAA (cf.FIGS. 5 a and 5 b). In cases of reduced levels of 5-HT and 5-HIAA,administration of compound 5′ was able to significantly increase 5-HTand 5-HIAA levels to normal values. Thus, administration of compound 5′compensates or over-compensates the diminishing effect on the 5-HT and5-HIAA levels.

The results exhibited above clearly demonstrate the neuroprotectiveeffect of compound 5′. The advantageous findings show that compound 5′is capable of compensating the harmful effect of neurotoxins and is ableto increase the 5-HT and 5-HIAA levels. Thus, it has been proven thatthe compounds of the present invention can be used as drugs in order totreat, for instance, Parkinson, Alzheimer, Chorea Huntington ordepression.

1. A drug combination comprising: a pharmaceutically effective amount ofat least one fatty acid for treating diabetes mellitus Type I, diabetesmellitus Type II, polyneuropathy, heavy metal poisoning, cerebralishemic disease, depression, and stroke, said at least one fatty acid isselected from the group consisting of linolenic acid, γ-linolenic acid,dihomo-γ-linolenic acid, α-linolenic acid, (R,S)-lipoic acid, (S)-lipoicacid, (R)-lipoic acid, linoleic acid C1-C7 alkyl ester, γ-linolenic acidC1-C7 alkyl ester, dihomo-γ-linolenic acid C1-C7 alkyl ester,α-linolenic acid C1-C7 alkyl ester, (R,S)-lipoic acid C1-C7 alkyl ester,(S)-lipoic acid C1-C7 alkyl ester, (R)-lipoic acid C1-C7 alkyl ester,(R,S)-6,8-dithiane octanoic acid C1-C7 alkyl ester, (R)-6,8-dithianeoctanoic acid C1-C7 alkyl ester, and (S)-6,8-dithiane octanoic acidC1-C7 alkyl ester, together with at least one nucleoside and/ornucleotide compound selected from the group consisting of uridine,deoxyuridine, uridine monophosphate, and deoxyuridine monophosphate, orpharmaceutically acceptable salts of said combination.
 2. The drugcombination according to claim 1, further comprising suitablepharmaceutically acceptable carrier, excipient, adjuvant and/or diluent.3. The drug combination according to claim 1, wherein the fatty acid is(R,S)-lipoic acid, (S)-lipoic acid, (R)-lipoic acid and/orpharmaceutically acceptable salts thereof, (R,S)-lipoic acid C1-C7 alkylester, (S)-lipoic acid C1-C7 alkyl ester, (R)-lipoic acid C1-C7 alkylester, (R,S)-6,8-dithiane octanoic acid C1-C7 alkyl ester,(R)-6,8-dithiane octanoic acid C1-C7 alkyl ester, and (S)-6,8-dithianeoctanoic acid C1-C7 alkyl ester.
 4. The drug combination according toclaim 1, wherein said drug combination is suitable for intravenous,intraperitoneal, intramuscular, subcutaneous, mucocutaneous, oral,rectal, transdermal, topical, intradermal, intragastral, intracutaneous,intravaginal, intravasal, intranasal, intrabuccal, percutaneous,sublingual administration or for inhalation.
 5. The drug combinationaccording to claim 1, wherein the drug combination is (R,S)-lipoic acid,(S)-lipoic acid, (R)-lipoic acid, (R,S)-lipoic acid C1-C7 alkyl ester,(S)-lipoic acid C1-C7 alkyl ester, (R)-lipoic acid C1-C7 alkyl ester,(R,S)-6,8-dithiane octanoic acid C1-C7 alkyl ester, (R)-6,8-dithianeoctanoic acid C1-C7 alkyl ester, and (S)-6,8-dithiane octanoic acidC1-C7 alkyl ester, with uridine, deoxyuridine, uridine monophosphate, ordeoxynridine monophosphate, or pharmaceutically acceptable salts of saidcombination.
 6. The drug combination according to claim 1, wherein saiddrug combination is in a pharmaceutically effective concentration in therange of 1-15000 mg.
 7. The drug combination according to claim 1,wherein said drug combination is in a pharmaceutically effectiveconcentration in the range of 100-1000 mg.
 8. A drug combinationcomprising: a pharmaceutically effective amount of at least one fattyacid, said at least one fatty acid is selected from the group consistingof linoleic acid, γ-linolenic acid, dihomo-γ-linolenic acid, α-linolenicacid, (R,S)-lipoic acid, (S)-lipoic acid, (R)-lipoic acid, linoleic acidC1-C7 alkyl ester, γ-linolenic acid C1-C7 alkyl ester,dihomo-γ-linolenic acid C1-C7 alkyl ester, α-linolenic acid C1-C7 alkylester, (R,S)-lipoic acid C1-C7 alkyl ester, (S)-lipoic acid C1-C7 alkylester, (R)-lipoic acid C1-C7 alkyl ester, (R,S)-6,8-dithiane octanoicacid C1-C7 alkyl ester, (R)-6,8-dithiane octanoic acid C1-C7 alkylester, and (S)-6,8-dithiane octanoic acid C1-C7 alkyl ester, togetherwith at least one nucleoside and/or nucleotide compound selected fromthe group consisting of uridine, deoxyuridine, uridine monophosphate,and deoxyuridine monophosphate, or pharmaceutically acceptable salts ofsaid combination.